Harrigan made his first stage appearance in 1867 at the Olympic, a San Francisco "melodeon", as that city's variety theaters were then known. A brief partnership with comic Sam Rickey was followed by a fourteen-year stage career with Tony Hart, whom he met in Chicago in 1870. Although Harrigan wrote the lyrics and stage patter, the diminutive Hart's charm and singing talent played a large role in the duo's success. Harrigan and Hart went in 1871 to Boston, where they had their first big success at John Stetson's Howard Athenaeum. They then moved on to New York, where they first worked with Tony Pastor before beginning a long run at Josh Hart's Theatre Comique. By the mid-1870s they began moving from the variety show toward musical theatre. Harrigan's sketches on the Comique's crowded bill featured comic Irish, German and black characters drawn from everyday life on the streets of New York. Their breakthrough hit was the 1873 song and sketch "The Mulligan Guard". It became their signature piece, and they featured it in many of their slapstick skits and plays. In 1876, Harrigan took over the Comique himself, along with Hart and manager Martin Hanley. By 1878, with The Mulligan Guard Picnic, Harrigan & Hart settled down on Broadway and performed in seventeen of their shows over the next seven years. Though still broad and farcical, these shows featured music that was integrated with a more literary story line, together with the dialogue and dance, and the shows began to resemble modern musical comedy. Harrigan wrote the stories and lyrics, and Braham wrote the music. He died in New York on June 6, 1911.
Harrigan married Annie Braham, on November 18, 1876. Their family continued in his footsteps, as son William Harrigan, daughter Nedda Harrigan, and granddaughter Ann Connolly all became Broadway performers.