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In collaboration with others at Marvel—particularly co-writers and artists Jack Kirby and Steve Ditko—he co-created iconic characters, including Spider-Man, the X-Men, Iron Man, Thor, the Hulk, Ant-Man, the Wasp, the Fantastic Four, Black Panther, Daredevil, Doctor Strange, the Scarlet Witch, and Black Widow. These and other characters' introductions in the 1960s pioneered a more naturalistic approach in superhero comics. In the 1970s, Lee challenged the restrictions of the Comics Code Authority, indirectly leading to changes in its policies. In the 1980s, he pursued the development of Marvel properties in other media, with mixed results.

Following his retirement from Marvel in the 1990s, Lee remained a public figurehead for the company. He frequently made cameo appearances in films and television shows based on Marvel properties, on which he received an executive producer credit, which allowed him to become the person with the highest-grossing film total ever. He continued independent creative ventures until his death, aged 95, in 2018. Lee was inducted into the comic book industry's Will Eisner Award Hall of Fame in 1994 and the Jack Kirby Hall of Fame in 1995. He received the NEA's National Medal of Arts in 2008.