When comparing GrafX2 vs Paint.NET, the Slant community recommends GrafX2 for most people. In the question“What are the best pixel art / sprite editors?” GrafX2 is ranked 2nd while Paint.NET is ranked 9th. The most important reason people chose GrafX2 is:
GrafX2 is scriptable using the Lua language, which can be used to automate tasks and add new functionality to it. The script library features advanced color reduction and enhancement tools, [palette analysis](http://eab.abime.net/showthread.php?t=76519), and much more.
Specs
Ranked in these QuestionsQuestion Ranking
Pros
Pro Scriptable using Lua
GrafX2 is scriptable using the Lua language, which can be used to automate tasks and add new functionality to it. The script library features advanced color reduction and enhancement tools, palette analysis, and much more.
Pro Supports many file formats
GrafX2 supports many file formats, including the popular gif and png, but also importing and exporting from deluxe paint, degas elite, and various other editors using custom formats.
Pro Very large number of tools and effects
Pro Free, open source, and cross-platform
GrafX2 is totally free to use, copy, and modify. It's available on Windows, Linux, Mac OS X, Haiku, AROS, MorphOS, SkyOS, Syllable, Mint, and a few more systems. Basically anything is supported by the SDL library.
Pro Palette color cycling
GraphX2 being based on older 256 bitmap software has inherited some tricks that modern pixel editors do not have . One of them being the ability to cycle color palette and produce animations and effects with it.
Pro Has a great palette tool
You can create gradients from one color to another, work in either RGB or HSL color space, save and load palettes, sort and organize palettes, and even work on "color cycling" images.
Pro Supports tileset addition and extraction
Pro Supports animations
The program has a basic support for animation using frames in newer versions. Graphics can be cloned and copied between frames and changed slightly.
See here how to animate with GrapfX2 https://www.youtube.com/watch?v=Gnq6zBZOqoM
Pro Has a customizable UI with themes support
Theme UI style can easily be changed from settings including buttons and colors.
Pro Drawing constraint mode for vintage 8bits machine
The program is able to enforce the pixel constraints of old machines (C64, ZX Spectrum, Apple II, Game Boy Color, etc.)
For example, in ZX Spectrum mode, only 2 different colors can be used in a 8x8 pixel block.
Pro Easy to learn and use
Unlike most photo editing software, Paint.NET is simple to learn and easy to use. This means less time is spent learning the in's and out's of Paint.NET and more time on photo editing. For those who only edit photos sporadically and don't have time to invest in learning complicated tools for editing, Paint.Net will suit your needs.
Pro Free software
There is no charge for this software; but donations are welcomed.

Pro Lightweight
Paint.net provides a streamlined but effective core tool set. Support for advanced and niche features is provided through modular plugins, allowing the user to install only what's needed.
Pro Actively developed
The project is active and being continually expanded and refined.
Pro Active and friendly community
The forums are filled with tutorials, as well as people who are friendly and eager to help.


Pro Plugins allow extra functionality
Plugins can be made by anyone in the community, and are offered for download on the forum. They extend the capabilities of Paint.NET to cover most tasks.
Pro HiDPI support
Paint.NET supports fully HiDPI displays, with no scaling problems.
Cons
Con Dated look and feel
It looks like it was never supposed to be used in the modern world.
Con Lack of modern features
Some modern features that are necessary to do pixel art creation for game dev work are lacking.

Con Only available on Windows
Paint.NET is only available on Windows.
Con No project-based interface
You can only edit a single image at a time in Paint.NET. For example, in other tools you can open 5 or a 100 images at the same time, and stack those windows in all directions.
Furthermore, when you are editing in Paint.NET you can only "view" a single image at a time, even though you can have multiple images open. This limits your zooming ability, as the image will go fullscreen quite quickly, and hide parts of it behind the floating toolbars which can not be embedded anywhere on the screen.
