While these are minor things, I feel they help the overall experience.
First off are the window and UI elements scaling. By default, the screen scaling is set 200%, and the UI to 100% - this means that when you zoom in to 100% on your work, it'll be at twice of its actual size. So I have it set to the opposite instead (screen 100%, UI 200%), this way 100% is full size, instead of 50%.
With these settings, you can also just get rid of the preview window, since it will just unncessarily take up space (unless you are working on a large piece, then it's probably better to keep it).
Something else you can do, is set both to 100%. Then you will end up with this:
This is terrible on a reasonably sized screen, but on a really small one it can really help, especially if you're working on an animation and need the timeline (layers/frames panel) visible at all times.
Lastly, I like to set the checked background to #808080 and #858585. This is just a personal preference (like most things here) - I found the default too contrasty.
There's not too much to do here other than moving the timeline around. If I'm on a small monitor and not working on something with a lot of layers, then I'll just hide it most of the time; if it's a static image with lots of layers, I'll move the timeline to the right side, and when it comes to animation then I'll just keep it in the default bottom position.
I have my keybindings set up MOBA style on the top number row:
` - quick eraser
1 - line tool
2 - bucket
3 - rectangle select
4 - magic wand
These are the ones I switch between the most. I sometimes use the brush tool or the rectangle tool, but not enough to warrant a place in the top master MLG row of dank numbers. The timeline I navigate with Shift + WASD, like so:
Lastly, layer properties are Shift + E and cel properties are Shift + Q.
Having the keybindings set this way, I rarely have to lift my left hand of the keyboard, which means efficiency.
So there you have it. This is just meant to be an example of what you can do with changing some basic settings, but you have a lot more options also.
What matters is that you don't settle for the defaults. Everyone has their own preferences, and I feel the Aseprite's defaults are pretty sane, but a lot of times they will just be unconfortable. Just by setting up basic stuff and learning the keybindings, you can speed your flow considerably.
Also, try out Aseprite if you are doing pixel art. It's good. :)