I once ran a successful Mutants and Masterminds campaign a few years ago. I don't think you necessarily need a fleshed out setting to begin with, since superhero stories are ubiquitous and take place in more-or-less the real world with added weirdness. Players will be pretty much familiar with all the basic assumptions out of the gate, unless you change them.
You really just need to decide how common superheroes and supervillains are. In my game, I decided they were fairly rare, so the players were pretty much the only superhero team around. Villains were common enough for a new one to show up every week.
Furthermore, you don't really need to make a fictional city or buy a setting book. I just centered my campaign in Las Vegas, because it seemed like an unusual setting. I tell you what, it was eminently satisfying to have my players drown a giant lava spider in the fountain pool outside of Caesar's Palace. NPCs and special locations were only detailed as needed. I came up with a few off the cuff, as well.
I don't think there's one best way to run a game, and I certainly don't know if this way is right for you. All I know is, my campaign ended with one of my players plowing his motorcycle/spaceship into the face of a Lovecraftian horror and splattering its brains all over the moon. My players and I greatly enjoyed it, and from that, I consider it a rousing success.