Born of Irish parents in St. Louis, Missouri, he dropped out of school at age fifteen and started working in the art department of the St. Louis Republic, where he created his first comic strip, Alma and Oliver. In 1905 he headed for New York City and a job with the prestigious New York World, where he worked on several short-lived strips, including Nibsy the Newsboy in Funny Fairyland, Panhandle Pete, Let George Do It, Snoozer, The Merry Marcelene, Ready Money Ladies and Cheerful Charlie. In 1904 he created The Newlyweds, about an elegant young couple and their baby, Snookums. This series, the first family strip in an American newspaper, became quite popular and caused rival newspaper the New York American to invite McManus to work for them, which he did from 1912 on.