Ruffalo joined the behemoth superhero franchise in 2012 when he portrayed Bruce Banner, aka Hulk, in team-up movie The Avengers — known as Avengers Assemble in the UK.
He has since appeared in various movies throughout the franchise and will reprise the role in this month's Disney+ series She-Hulk: Attorney at Law, in which Tatiana Maslany plays Banner's similarly super-powered cousin.
Watch: Mark Ruffalo in trailer for Marvel series She-Hulk: Attorney at Law
"[Marvel fatigue is] not something I worry about. I understand that these things run their course and then something else comes along," he said.
Ruffalo added: "But the thing Marvel has done well is that, inside the MCU, just as they do with comic books, they let a director or an actor sort of recreate each piece to their own style, their likeness.
Read more: The comedy influences on She-Hulk
"Marvel generally lets them bring that to the material. If you watch a Star Wars, you’re pretty much going to get the same version of Star Wars each time.
"It might have a little bit of humour. It might have a little bit of different animation. But you’re always, really, in that same kind of world. But with Marvel you can have a whole different feeling even within the Marvel universe."
There has been talk of Marvel fatigue throughout the studio's fourth phase of movies, which have seen projects released thick and fast on the big and small screens.
By the time Phase Four concludes with Black Panther: Wakanda Forever in November, Marvel will have released seven films and eight TV series in the space of less than two years.
She-Hulk counts Rick and Morty alumnus Jessica Gao as showrunner and is set to have a more overtly comedic tone than other recent Marvel properties, with Kat Coiro and Anu Valia sharing directing duties.
As well as Maslany and Ruffalo, the cast includes Jameela Jamil and Hamilton star Renée Elise Goldsberry, as well as returning Marvel faces Tim Roth as Abomination and Charlie Cox as Daredevil.
The first episode of She-Hulk: Attorney at Law will arrive on Disney+ on 18 August.
Watch: Mark Ruffalo teases new side to Bruce Banner in She-Hulk