In 1849, Morrissey ventured to New York City to challenge prizefighter Charley Duane. When Duane ignored him, and no other prizefighters were present at Isaiah Rynder's Empire Club saloon, Morrissey took on the house in fisticuffs. Rynders, a Tammany Hall politician, was so impressed that he hired Morrissey as a "shoulder hitter" (a fighter who enforced the will of a political-machine boss by intimidation or violence). Morrissey was nicknamed "Old Smoke" after a saloon brawl in which he and his opponent knocked over a stove and Morrissey was pinned over the coals, with smoke from his smoldering clothes permeating the room. Morrissey persevered to win the fight.

In 1851, Morrissey journeyed to California, where he won a lot of money at gambling and first appeared as a professional prizefighter, earning a $4,000 purse and $1,000 from a side bet. He was unsuccessful, though, in his attempt to conquer the gold-rich Queen Charlotte Islands, off the coast of British Columbia, with an armed schooner and a crew of hoodlums. Back in New York in 1853, Morrissey became the boxing "Champion of America" by defeating Yankee Sullivan in 37 rounds. (At the time, prizefights were bare-knuckle events, with rounds lasting until one man fell down, and the match ending only when one boxer could did not return on his feet to the center of the ring.)

Working again for Tammany Hall, Morrissey organized a gang of shoulder-hitters, which primarily battled Bill Poole's American party (Know-Nothing) gang. In July 1854, Poole defeated Morrissey in a boxing match. Street fights between the two gangs continued, resulting in the deaths of several members, including Poole in March 1855. Morrissey was charged with the murder, but released. In a well-publicized prizefight in October 1858, Morrissey defeated John "Benicia Boy" Heenan at Long Point, Canada, before a crowd of 2,000, and pocketed $5,000 from a side bet. After the Heenan bout, Morrissey retired from the boxing ring as the champion.