I loved Prison Break back in the day but I do wish they could go back in time and rework things.
First of all, there are far, far too many episodes in one single season. If Breaking Bad taught us anything, it's that less is sometimes more. Season One is some of my favourite television ever (especially the latter few episodes), but Season Two features far, far too many plot twists and unnecessary filler that just serve to drag it out.
22 Episodes in Season One, 22 in Two, 13 in Three (which actually is a great length...) and 22 in Four. That's...a lot of episodes. Far too many.
I'd go back in time, purposefully cut short the length of each season to 13. By that estimation, they wouldn't be breaking out of Prison until the end of Season Two, which a third (and maybe a final season) dealing with their life on the run. Season Two was actually fine with the whole ManHunt thing and I enjoyed that, but it got ridiculous towards the latter third and become too convoluted for its own good. The first half especially is pretty good, actually.
Maybe even put 10 Episodes per season like Game of Thrones. It makes a huge difference, imo.