The Buffy the Vampire Slayer creator told SFX that he doesn't want a follow-up to "rehash" what worked in the first film.
Asked how Avengers 2 could top next month's superhero blockbuster, Whedon responded: "By not trying to. By being smaller. More personal, more painful.
"By being the next thing that should happen to these characters, and not just a rehash of what seemed to work the first time. By having a theme that is completely fresh and organic to itself."
Whedon joked that a sequel could take heed from crime classic The Godfather II "by having flashbacks to young Michael Andolini escaping Sicily to come to New York, where he will be called Corleone".
"Sequels are always better when that happens," he quipped.
Whedon added that he has strived to give each character in The Avengers, which brings together Iron Man, Captain America, Thor and Hulk, enough screen time to see "what makes them awesome".
"I want to know what makes them tick, what makes them flawed, what makes them fight - and ultimately, what makes them awesome," he explained. "I go to these movies for those moments when the heroes define themselves, either through action or deliciously overwritten speeches."
The Avengers (titled Marvel Avengers Assemble in the UK) opens in cinemas this April with Robert Downey Jr, Chris Evans, Chris Hemsworth and Scarlett Johansson leading the cast.
View the latest Avengers pictures in the gallery below: