He was co-owner and managing editor of the Chicago Tribune, and was Mayor of Chicago after the great fire of 1871. In 1853, Medill and Edwin Cowles started the Leader a newspaper in Cleveland, Ohio. (It was later absorbed by The Plain Dealer).
In 1854, the Tribune's part-owner, Captain J. D. Webster, asked Medill to become the paper's managing editor. Medill was further encouraged to come to Chicago by Dr. Charles H. Ray of Galena, Illinois, and editor Horace Greeley of the New York Tribune. In 1855, Medill sold his interest in the Leader to Cowles, and bought the Tribune in partnership with Dr. Ray and Cowles' brother Alfred.
Under Medill's management, the Tribune flourished, becoming one of the largest newspapers in Chicago. Medill served as its managing editor until 1864, when Horace White became editor-in-chief. At that time Medill left day-to-day operations of the Tribune for political activities.
But White clashed with Medill over the Presidential election of 1872. So, in 1873 Medill bought additional equity from Cowles and from White, becoming majority owner. In 1874, he replaced White as editor-in-chief.
Medill served as editor-in-chief until his death. Under Medill, the Tribune became the leading Republican newspaper in Chicago. Medill was strongly anti-slavery, supporting both the Free-Soil cause and Abolitionism.
Medill was a major supporter of Abraham Lincoln in the 1850s. Medill and the Tribune were instrumental in Lincoln's presidential nomination, and were equally supportive of the Union cause during the American Civil War. The Tribune's chief adversary through this period was the Chicago Times, which supported the Democrats.
He was appointed by President Grant to the first Civil Service Commission. In 1870, he was elected as a delegate to the Illinois Constitutional convention. As mayor, Medill gained more power for the mayor's office, created Chicago's first public library, enforced blue laws, and reformed the police and fire departments.
But the stress of the job impaired his health. In August 1873, he appointed Lester L. Bond as Acting Mayor for the remaining 3½ months of his term, and went to Europe on a convalescent tour. Medill was a strong Republican loyalist who supported President Grant for re-election in 1872.
The breach with White came because White supported the breakaway Liberal Republicans, reformists who nominated Horace Greeley for President. It was also at this time that Medill broke with Greeley.
In 1864, Medill left the Tribune editorship for political activity, which occupied him for the next ten years. In 1871, after the Great Chicago Fire, Medill was elected mayor of Chicago as candidate of the temporary "Fireproof" party, serving for two years.
Member Illinois Constitutional Convention, 1869.
Married Katharine Patrick, September 2, 1852, 3 children.