Are there any rules of thumb for the most comfortable seats on a long distance bus?

There is one aspect that no one referred. I noticed in my last trip and may be important for some.

Picking the first row of sits assures you that no one reclines the chair towards you.
Picking the last, before the back door allows you to recline your chair without bothering anyone.

This might be particularly important for night trips.

I’ve traveled extensively by long-distance bus, and can say from experience that the best seats really depend on what you’re looking for. Some bus carriers have two levels, some have outlets, most have wifi.

Front vs. Back

If noise is a concern, you’re better off closer to the front, as most buses these days have their engine in the back. Also, bathrooms tend to be in back, so unless you predict frequent bathroom visits, you’re better off up front for smell. You also generally have the worst view towards the back in a rear-engine bus, because having the engine in back means no rear windows. It doesn’t seem to matter much for vibration/bouncing where in the bus you are.

Left vs. Right

I’d pick the side of the bus depending on what you want to see, notably sunrise and sunset. In the northern hemisphere, the sun is always to the south, and regardless of hemisphere it rises in the east and sets in the west. If you’re going north and you want to catch the sunrise, that’s the right side of the bus. South, left side. North and trying to catch sunset, left side. South, right side. Going east the sun will be a little to your right, going west it’ll be to your left. You can see other features the same way. Say you’re taking a bus up the west coast and you want a chance to see the ocean. That’s west, so going north puts the coast on your left. Of course, if you’re planning on sleeping as much of the ride as possible, you might want to be on the opposite side from the sun.

Window vs. Aisle

This is really a matter of personal preference. Window gives you views and usually better access to the outlets, which tend to be along the wall, while aisle gives you a bit more space for your things. If you’re particularly social or need to keep an eye on the family, aisle also gives you better access to other people in the bus. In my experience, aisle tends to get more claustrophobic, because you get less window views. Unlike in an airplane though, where the windows are tiny, you’ll be able to see out the windows regardless of where you are.

I personally prefer the window, unless I’m sitting at my favorite seat, described below.

Seating Types

A good number of the big bus carriers don’t have assigned seating, so you’re stuck showing up early and hoping for something good. A few of the big carriers provide reserved seating for another dollar or two, which lets you pick your seat in advance out of a number of numbered, slightly more comfortable seats to the front. A few carriers also have some seats with tables, which is handy if you want to get work done or comfortably seat your family. If it’s leg room you’re after, you can get seating with your feet by the stairs, leaving more room for yourself and your things. This is often called balcony seating. They’ll rarely let you leave things on the stairs themselves though. Note that reserved, balcony or table seating will usually cost from $1 to $3 more per ride, which tends to be well worth it for an hours-long trip.

My personal favorite perk is provided by Megabus, and probably a few other carriers as well: panoramic window views at the front of the upper level. Rather than putting regular windows at the front of the upper level of the bus, someone thought to put a giant window across the entire front, offering amazing views for $5 to $9 more, which for a long ride buys you hours full of entertainment, and the extra space up front. Try finding amusement park tickets for under $10. There’s also a sun shield you can pull down over the window if you want to go to sleep.

The real advantage of buying reserved seats is you know what you’re going to get ahead of time, and never have to risk smelly bathroom-side seats if you show up at the end of the line.

The Takeaway

You’re basically always best off closer to the front, which is why that’s where they put most of their reserved seating. Pick your side based on the views and the sun, and how much sleep you’re planning on getting. Pick whether you want a window or aisle seat depending on whether views or the ability to get up and move are more important to you, though you’ll generally not be doing much getting up and moving on such a bus. I’d always go with reserved seating, because it guarantees you a good seat of your choice rather than leaving it up to chance. Finally, if you have such an opportunity, pick one of the four front seats on top, and you’ll love the views. Plus, the panoramic glass means they’re all window seats, so you can go with one of the middle two aisle seats for extra space.

Enjoy your trip, and happy travels!

The three in-line seats next to the bathroom FTW. Nap time. I’m short and can get comfortable almost anywhere, so your millage may vary.

Most of the journey will be highway miles, at least in the States, and if you’re like me you won’t be able to sleep sitting up or through any of the stops anyway. So if you can get the couch in the back all to yourself, take it. Because none of the seats are “comfortable”.

If you can’t, then differ to other answers that mention where you’d want to be relative to the wheel base, not the sunny side, and isle seats.

On a personal note, because you’re considering long distance buses, the three and a half day trip I took across the States is something that I will never, ever, repeat. It’s on my top ten list of things I’d be willing to criminalize myself to avoid if necessary.

In hot areas, check for ventilation openings/emergency exits in the ceiling, open it, and seat yourself in the aisle one or two seats behind it for some natural ventilation.

On some mountain routes (I’ve experienced this in Switzerland) the back of the bus swings out over the edge of the road on bends — and it’s a long way down, so sit near the front if you’re afraid of heights. These buses often have the back axle a long way forwards, which makes my next point more significant.

Leverage suggests that you should sit between the axles if you’re worried abut motion sickness. If the back axle goes over a bump and you’re on the back row, you can be quite a long way behind the axle, increasing the motion due to the bump. Also right at the back the engine vibrations can be more noticeable, again not good if you get travel sick.

The seats can get rather warm if they’re directly over the engine (e.g. many UK urban buses, but also on long-distance routes depending on the configuration). This could be good or bad for you depending on whether you feel the cold. On really old or badly maintained buses there may be a smell of hot oil in this area — again one to avoid if you get sick.

One other thing to consider when choosing which side of the bus to sit on is where the sun will be during your trip, based on the time of day and overall direction of travel. Sitting on the sunny side of the bus can be less comfortable in terms of both temperature and glare, so I generally choose to sit on the shady side if possible.

If motion sickness is a consideration
As a child suffering from motion sickness I would always try to sit between or above the wheels. In modern buses you do not see the wheels but the area between the wheels is still the area with the least swaying motions.

Forward view
If you want forward view, the front seat on the other side as the driver is great. In some buses there will be several to chose from as they are on different levels.
An other advantage of the front row seat on many coaches (as mentioned by @nsn in his answer) is that there is no row further forward with seats that recline into your face.
A disadvantage of the front seats, specially in countries with many road accidents, is that you are more likely to suffer, (or die,) if the bus hits something head on.

My last multiple day ‘bus’ tour was in a 20 seater that was filled with the maximum number of passengers so the ‘guide’ seat next to the driver needed to be used. I loved it though it had less leg room and no place to store a carry-on bag. The views were amazing.

Traveling with a group
But for those who like to hang out together while in a bus, the back seat still offers the best options.
Some buses (the kind that have been used as city bus in the early part of their life) have sets of seats where two face backward, making a group of four for friends, without having to be in the back of the bus.

Window or aisle seat
View to the left or the right does make a difference but unless you know where the best views will be, it will be a guess.
I prefer aisle seats, as with those you have pretty good views one way and acceptable ones the other, while window seats give good views one direction and almost nothing the other way.

Other reasons to chose window or aisle is the space you get and the fact that others will pass.
Those that need more than average space, for reasons of build, size or because being stuck in a small space is uncomfortable, the aisle seat is the prefered one.
When needing to get up several times, bathroom or just stretching your legs, you will find the aisle seat the easier one, specially when sitting next to a stranger or when your traveling companion is likely to sleep most of the time.
When sleeping, or trying to, in an overnight bus, the window seat allows for more positions to relax, including leaning against the window.
Sitting in the window seat you will less likely be disturbed by people walking past.
And when in a bus/coach where not everybody is to be trusted, the window seat also gives less access to your things for people walking past.
The trade off is that you have less access to and less control over the items stored overhead.

Left of right of the bus
If you want the best views out of the side windows of a bus, check where the best views will be.
Other considerations are where the sun will be, as sitting on the sunny side on a hot day and looking into the glare for most of the day will be less pleasant. This is made less important if the bus has coating on the windows and if it has good airconditioning.

Not all buses are build the same, exceptions happen
If there is the option to reserve a seat before comming into the bus, remember not all buses are the same.
In some cases the aisle seat behind the driver is a good choice, if you can see out to the front of the bus. On many buses the view to the front is over the driver and the space for the feet is nice.
In some buses you have no forward view at all and less space for your feet.

My grandmother had a knee that she could not bend. She would request the seat next to the emergency exit as that would have enough space for her to sit. But in some cases the seat was not suitable and she had to change the request while getting into the bus the first time. She traveled bus tours for many years, with a company that made the people move to the next seat after every stop, so that all people got the better and the worse seats. She did get freedom from that moving, but it would not always get her a good seat.

Double decker buses, up or down
If you want steady, not too much sway, top level of double decker bus is not good — the movements of the bus will be 3 to 10 times as strong on the higher floor.
Someone suffering from motion sickness should check whether they feel alright on the top floor of a bus. Not all sufferers will need to avoid top floors, and those who suffer in some buses might feel alright in others.

The views are better, specially those from the front seats. And often there are two sets of front seats available.

Extra tips for those who suffer from motion sickness
Watch what you are eating and drinking before and during the trip.
Avoid foods that make you want to burp, check whether you react badly on fatty foods, foods that make you fart (also on the day before a travel) and other foods that might upset the system.
(I would not believe it, but some people claim that drinking carbonated drinks to make you burp helps in not getting sick. Worth trying out if you suffer badly.)
There might be foodstuffs that help you fight attacks, like mints or boiled sweets you suck on. Talk with people in your family if there are more that suffer the sickness as well, as there are bound to be stories of what helps and what to avoid.

If there is a vent for the airconditioning you can aim, have it at least at its lowest level and aimed just in front of your face, unless you want it fuller open and aimed differently of course.
When there are only fixed vents, you may want to chose your seat to have one near, as long as the air coming out smells nice.
Also, the seats behind and below the escape hatch when opened will have a better air quality than the average for the bus.

For those of us who suffer badly, frequently or violently, warn the driver and ask for him to open the door, when safe to do so, on request.
Sometimes a flow of fresh air will calm down the urge, in other times being able to aim out of the bus will be much easier than using a bag.
And always carry a suitable container to accept more than one time of being sick, or a series of ‘just big enough’ ones.
Best if they are easy to close safely and sturdy enough to withstand the liquid. Paper bags are OK as long as you can dispose of them soon after use.
Strong plastic bags will keep much longer. But smells coming out will not help you nor other people around, so close and keep closed unless needed.

Most people suffering motion sickness can not read on a bus, some exceptions can read but can not stand being bored. So do test and it may turn that you can read.
Always take something that takes away boredom, like music or a spoken book on headphones, or use your brain to distract you, like dreaming up a story or doing your tables of multiplication.

I’d say, sit at least a couple of rows away from the bathroom; and skip the first row behind the driver than the door; they sometimes have less leg room and no view (at least behind the driver).

If you know where you are going, sitting on the curb side or street side can have different views.

(personal experience) For example, when in a bus between Sorrento and Amalfi (Italy), it is more fun sitting on the sea side than on the mountain side