I've often returned FL rentals to different airports (usually pick up in Tampa and return to Ft. Myers).
It's not a HUGE hassle to travel between Orlando and Tampa...for the most part. However, I4 can be VERY unpredictable. I've made it between the two in as little as 50 minutes, but it has also taken me just shy of 4 hours because of accidents / construction.
Some things to consider are:
-day of the week and time of day (both can still vary though)
-what the time/hassle is worth to you. I am all about cost savings, but somewtimes (esp. when precious vacation time is concerned it is worth it to me to pay for the convienance if I think it will make my trip more enjoyable, but that's just me)
-will you rent a car anyway? If you are on the fence then the cost of the car vs riding Magical Express for free could balance out the flight difference
-do you have any other reason to go to Tampa? If you wanted to work in a beach day or trip to Busch Gardens then it might be worth it.
-to me (and this probably is just silly) MCO is part of the trip. It goes back to when I was a kid I think, but I just LOVE LOVE LOVE getting off the plane, feeling the warm air, taking the people mover, seeing all the themed gift shops and the people with the Mickey gloves. Again, silly, but sets the tone. Of course the flip side is the sun-burned families screaming at each other because they are all sick of being together, waiting in lines and sharing a bathroom waiting for their return flights LOL)
-of you are renting a car...did you look into picking the car up in Disney? We wanted a car on our last trip because our son was 8 months old. We ended up taking ME to Disney and then picked our car rental up in Downtown Disney. It saved us over $200.00 doing that and we were able to get an SUV instead of a midsize.
-Did you check into Sanford Airport? It is also about 45 minutes from there to Disney (again traffic/construction not included in that time), but they have decent car rental rates, it's an "easy airport" and discounted airlines like Allegiant fly in there.
Just a few options. That's my long answer. The short answer is if you need to save the money then no it is not "too" bad to drive between Tampa and Orlando. Either way, have a fabulous vacation!