The biggest difference between Regional / Mainline flying is stage length. Much of the “work” in an airline flight is the preflight/postflight procedures, ie Takeoff/Landing.
Airline pilots are only paid for “flight hours” which is the time the door is closed at the gate till it opens at the destination (slight variances between airlines, but the idea is the same), so each time while you are waiting to board and unload an aircraft that you see the crew standing around, that time is on them, they are only paid for the actual flight time.
This is really the main difference, ironically, the regional flying is generally much more work, longer days. In it’s extreme an RJ pilot may do 5 legs in one day and still credit less flight time than the pilot that loaded up a 777 and commenced a one leg 10hr flight. (not to mention the 10hr flight required three pilots so 1/3 of that time you are napping/out of the cockpit).
Now add to that the fact that airline contracts are generally built with the idea that the more seats(revenue) the more pay per flight hour, it adds up to leaving a lot of $$$ and extra effort on the table to stay as a regional pilot instead of pursuing a job at the majors.
Now that being said, many find the RJ job adequate and perhaps even better than “starting over” at a later age in life because all airlines operate purely on seniority, so a very senior RJ pilot who doesn’t commute may very well do as well or better as a junior Major airline pilot, but with even a few years at a major, they will quickly surpass the RJ in pay and effort required to earn those $$$$.
The last thing to consider as a permanent regional pilot is that, at it’s essence you are working for a contractor of a major airline. Look at the RJ companies and with the possible exception of Skywest and Horizon, most have had a very tumultuous history, as the major airlines sell the tickets, control the schedules, and make the “contract airlines” compete against each other for flying. This leads to frequent base openings and closings over significant periods of time as the regional companies have very little control over their own destiny. At least with a major airline, you are on a ship with it’s own destiny, bases and fleets may come and go (not nearly as frequently as regionals), but either your company survives or dies with you attached.