Ketcham was born in Seattle on March 14, 1920. He stated that he knew when he was 6 years old that he wanted to be a cartoonist. He described watching a friend sketch the cartoon character Barney Google and "I couldn't wait to borrow his 'magic pencil' and try my own hand at drawing these comic-strip characters. It was a major discovery, and I was floating on air with excitement" (Seattle Post-Intelligencer).
Ketcham graduated from Queen Anne High School and entered the University of Washington in 1938. He dropped out after his first year to become an animator for films in Hollywood. He worked on Woody Woodpecker for Walter Lantz, and on the animated films Pinocchio, Bambi, Fantasia, and Donald Duck for Walt Disney.
During World War II, Ketcham served in the Navy, creating cartoons for posters, training materials, and war bond campaigns. After the war he worked as a freelance cartoonist and resided in Carmel, California. In 1951, after his 4-year-old son Dennis demolished a room instead of taking his nap, Ketcham's wife, Alice, told him, "Your son is a menace."
Dennis the Menace eventually ran in 1,000 newspapers, in 48 countries, and in 19 languages. Books of cartoons, comic books, a television series, a musical, and a motion picture spun off from the comic strip.
In March 2001, Ketcham stated, "It's a joyful pursuit realizing that you're trying to ease the pain of front-page news or television" (Seattle Post-Intelligencer).