Nolan's Batman movies all had multiple villains. Batman Begins had Ra's, Scarecrow and Carmine Falcone. The Dark Knight had The Joker, Two-Face and Sal Maroni. The Dark Knight Rises had Bane, Catwoman and Talia.
What made them work is because Nolan wrote or co-wrote the story and then added in the villains that best suited that story. Not the other way around. Ra's and Scarecrow made sense for Begins, for example, because the theme of the movie was fear and Ra's/Scarecrow just exemplified that. The Dark Knight was about escalation and chaos, and what better villain to use for chaos than The Joker? Two-Face, and more to the point Harvey Dent's gradual dissolution into Two-Face, fights into the theme of escalation and gradual chaos. With Rises, it was basically a disaster movie, and the theme was very much about pain and overcoming pain, and what better villain to deal with that than Bane? Etc etc.
With most superhero movies, it seems like villains are randomly picked. Spider-Man 3 is a good example of that. Sandman and Venom had no reason to team up with each other beyond a mutual hate/disdain for Spider-Man, for example. Beyond that, it just didn't make any sense. The same can be said for most superhero movies with multiple villains. If you're going to go that route, you better make sure it fits within the context and thematic foundation of the story.