Thats a pretty subjective question and the answer might change based on how you rank the following: On time performance, frequent flier program, airplane types and age, interline agreements (for when things go oh so wrong on your trip), partner airlines, route network. For example Delta is great at getting you to where you need to go on time even though they have major hubs in snowy areas but they fly older planes and have a terrible frequent flier program. I've also not has as good of luck with Delta finding cheap airfare sales
Domestically I won't fly Spirit: no interline agreements, terrible on time performance, limited route network redundancy (related to the previous), above average lost bags and by far, the most complaints. I'd have to think long and hard about Frontier (Whose current CEO was in charge of Spirit for a long time) and Allegiant but I've never been in a position where I didn't have decent alternatives as I'll fly anyone else.
If you want to get really complicated you can also look at seat configuration of the planes on the route. If I fly with my wife I'll look for flights with a 2-3-2 or 2-4-2 seat configuration over a 3-3-3