Always have the OS on a seperate drive with just the OS (and potentially the few software that prefer to run from C drive). Or at the very least on a seperate partition.
This includes putting directories like My documents, pictures, etc on the other drive. May take a few extra minutes at the start to remap those locations, but worth the effort.
It'll still behave the same, just that everything will be stored on another drive. The exception is when programs put stuff in that hidden appdata folder, they will be on C drive unfortunately.
If something goes wrong and you need to do stuff to Windows like reinstall, there will be no worries about your files since they'll be seperate. Obviously copying and backing up the appdata stuff is the exception.
My current OS drive is a standalone 250GB SSD and it's never gotten close to full running Windows 10. Going forward I'll have a 1TB M.2 on the new build (and 2TB M.2 for other storage), since the 1TB is overkill for OS, I'll just partition it and use some of it for some storage.