At age 19, Wilkie joined the staff of the Chicago Times as a reporter. His father, Frank B. Wilkie, was an editorial writer at the newspaper; the two traveled to Europe and served as the Times' European correspondents. Upon returning to the United States, Wilkie joined the staff of the Chicago Tribune, where he initially served as financial editor and later city editor. While at the Tribune, Wilkie hired satirist Finley Peter Dunne.
On August 8, 1890, while working for the Tribune, Wilkie wrote a pseudonymous article that first described the Indian Rope Trick. Featured on the front page of the paper's second section, it was soon picked up by newspapers throughout the United States and United Kingdom, and it was translated into nearly every European language. Soon a number of people claimed to remember having seen the trick as far back as the 1850s. Four months later, the Tribune printed a retraction noting the story had been "written for the purpose of presenting a theory in an entertaining form." However, the notice of the hoax garnered little attention, and the myth of the Indian Rope Trick persisted for years. When The People's Friend, a British weekly magazine, contacted the Tribune in order to contact individuals mentioned in the story, Wilkie wrote a personal note: "I am led to believe that the little story attracted more attention than I dreamed it could, and that many accepted it as perfectly true. I am sorry that anyone should have been deluded."
By 1893, Wilkie had moved to London to work on behalf of an American railroad and steamship office. He returned to the United States in 1897 to go into private business. Sometime in these years he began working with the United States Secret Service, though those who knew him personally were not aware of the fact until he became Chief of the bureau.