Born in Seattle, Washington, Ketcham was the son of Weaver Vinson Ketcham and Virginia King. His great-grandfather was James Weaver, who ran for President twice on third party tickets in the late 19th century. When he was six years old, his father had a guest over for dinner who was an illustrator. After dinner, he showed the youngster his "magic pencil" and drew some illustrations. Ketcham was immediately hooked, and soon his father set up a small desk in the closet of his bedroom at which he could draw. After graduating from Queen Anne High School in 1937, he attended the University of Washington but dropped out after his first year and hitchhiked to Los Angeles, hoping to work for Walt Disney.
Ketcham started in the business as an animator for Walter Lantz and eventually Walt Disney, where he worked on Pinocchio, Fantasia, Bambi and several Donald Duck shorts. During World War II, Ketcham was a photographic specialist with the US Navy Reserve. He also created the character Mr. Hook for the Navy during World War II and four cartoons were made (one by Walter Lantz Productions in color and three by Warner Bros. Cartoons in black and white). Also while in the Navy he began a camp newspaper strip, Half Hitch, which ran in The Saturday Evening Post beginning in 1943.
After World War II, he settled in Carmel, California, and began work as a freelance cartoonist. In 1951, he started Dennis The Menace, based on his own four-year-old son Dennis Ketcham. Ketcham was in his studio in October 1950, when his first wife, Alice Mahar, burst into the studio and complained that their four-year-old, Dennis, had wrecked his bedroom instead of napping. "Your son is a menace," she shouted. Within five months, 16 newspapers began carrying the adventures of the impish but innocent "Dennis the Menace." By May 1953, 193 newspapers in the United States and 52 abroad were carrying the strip to 30 million readers.
When he retired from drawing the daily, Ketcham's former assistants, Marcus Hamilton and Ron Ferdinand, took over. At the time of Ketcham's death, Dennis the Menace was distributed to more than 1,000 newspapers in 48 countries and 19 languages, by King Features Syndicate.