Harrison was first elected mayor in the 1897 Chicago mayoral election. He would win election to three consecutive additional two-year terms in 1899, 1901, and 1903. Harrison was sworn-in as mayor on April 15, 1897. Like his father, Harrison did not believe in trying to legislate morality. As mayor, Harrison believed that Chicagoans' two major desires were to make money and to spend it. During his administrations, Chicago's vice districts blossomed, and special maps were printed to enable tourists to find their way from brothel to brothel. The name of one Chicago saloon-keeper of the time supposedly entered the English language as a term for a strong or laced drink intended to render unconsciousness: Mickey Finn. However, Harrison was seen as more of a reformer than his father, which helped him garner the middle class votes his father had lacked. One of Harrison's biggest enemies was Charles Yerkes, whose plans to monopolize Chicago's streetcar lines were vigorously attacked by the mayor. This was the beginning of the Chicago Traction Wars, which would become a major focus of his administration. During his final term in office, Harrison established the Chicago Vice Commission and worked to close down the Levee district, starting with the Everleigh Club brothel on October 24, 1911. Despite prolonged and damaging international press coverage blaming his lax municipal enforcement for the 602 lives lost in the Iroquois Theatre fire on December 30, 1903, Harrison hoped to become the 1904 Democratic nominee for President of the United States. However, the nomination went to Alton B. Parker, who was soundly defeated by Theodore Roosevelt. Harrison declined to seek a fifth consecutive mayoral term in 1905, and was succeeded by fellow Democrat Edward Fitzsimmons Dunne on April 10, 1905.
Between mayoralties
, attempting to stage a return to office, Harrison unsuccessfully challenged Dunne for the Democratic mayoral nomination.
Second mayoralty
, Harrison was elected to a four-year term as mayor. He as sworn-in for his fifth nonconsecutive term as mayor on April 17, 1911. In 1914, Harrison convinced the city council to establish a Commission for the Encouragement of Local Art to purchase works of art by Chicago artists. Harrison personally purchased artwork from painters such as Victor Higgins and Walter Ufer. Harrison sought a sixth overall term as mayor in 1915, but was defeated in the Democratic primary by Robert Sweitzer, who went on to lose the general election to Republican William Hale Thompson. Harrison was succeeded in office by Thompson on April 26, 1915. In 1915, when Harrison left office, Chicago had essentially reached its modern size in land area, and had a population of 2,400,000; the city was moving inexorably into its status as a major modern metropolis. He and his father had collectively been mayors of the city for 21 of the previous 36 years.
Post-mayoralty
Harrison published two autobiographies. One of these, a memoir entitled Growing Up with Chicago, was published in 1944. Harrison died on December 25, 1953 in Chicago, and is buried in Graceland Cemetery. His papers are held by Chicago's Newberry Library.