Unless you have a ton of bags or lots of kids. The bus operates very reasonable hours to/from EWR to midtown (4am - 1am) and probably saves you time vs. the time to get from terminal to rental car pickup/dropoff point.
I think of only of few early AM flights (CO to IAH, US to CLT and AA to MIA) the bus wouldn't work for but PATH is an option to a cab in Newark (if you are leaving from midtown 34th St South).
Unfortunately, EWR is not convenient getting from Terminal C to rental cars during off-peak times.