As a writer and editor, Lee was key to the ascension of Marvel into a comic book titan in the 1960s when in collaboration with others he created superheroes who would enthrall generations of young readers.
Lee's daughter J.C. Lee confirmed the death to Reuters.
Americans were familiar with superheroes before Lee, in part thanks to the 1938 launch of Superman by Detective Comics, the company that would become DC Comics, Marvel's archrival.
Lee was widely credited with adding a new layer of complexity and humanity to superheroes. His characters were not made of stone - even if they appeared to have been chiseled from granite. They had love and money worries and endured tragic flaws or feelings of insecurity.
"I felt it would be fun to learn a little about their private lives, about their personalities and show that they are human as well as super," Lee told NPR News in 2010.
He had help in designing the superheroes but he took full ownership of promoting them.
His creations included web-slinging teenager Spider-Man, the muscle-bound Hulk, mutant outsiders The X-Men, the close-knit Fantastic Four and the playboy-inventor Tony Stark, better known as Iron Man.
Dozens of Marvel Comics movies, with nearly all the major characters Lee created, were produced in the first decades of the 21st century, grossing over $20 billion at theaters worldwide, according to box office analysts.
Spider-Man is one of the most successfully licensed characters ever and he has soared through the New York skyline as a giant inflatable in the Macy's Thanksgiving Day Parade.
Lee, as a hired hand at Marvel, received limited payback on the windfall from his characters.
In a 1998 contract, he wrestled a clause for 10 percent of profits from movies and TV shows with Marvel characters. In 2002, he sued to claim his share, months after "Spider-Man" conquered movie theaters. In a legal settlement three years later, he received a $10 million one-time payment.
Hollywood studios made superheroes the cornerstone of their strategy of producing fewer films and relying on big profits from blockbusters. Some people assumed that, as a result, Lee's wealth had soared. He disputed that.
"I don't have $200 million. I don't have $150 million. I don't have $100 million or anywhere near that," Lee told Playboy magazine in 2014. Having grown up in the Great Depression, Lee added that he was "happy enough to get a nice paycheck and be treated well."
In 2008, Lee was awarded the National Medal of Arts, the highest government award for creative artists.