In the late 1940s, we meet Frankie Majcinek, known as Frankie Machine (Frank Sinatra), as he returns to the vibrant South Side of Chicago, a neighborhood predominantly populated by Polish Americans, after completing a six-month stint in a federal narcotics hospital. The locals at Antek's Tug `n' Maul Tavern, his beloved bar, are delighted to see him again, especially his loyal friend, the "lost dog finder," Sparrow (Arnold Stang). However, when Nifty Louie Fomorowski (Darren McGavin), his former drug supplier, offers him a free fix, Frankie stands firm in his commitment to sobriety, declaring to Sparrow that he has definitively kicked drugs and now dreams of becoming a drummer for a big-name band.
Proudly exhibiting the drums received during his treatment, Frankie heads home to his rooming house, where he lives with his manipulative wife, Zosch (Eleanor Parker). Zosch, bound to a wheelchair, has effectively kept Frankie under her control for the past three years, invoking guilt over the accident that left her injured due to his reckless driving while intoxicated. Doubting his aspirations of becoming a musician, Zosch urges Frankie to return to dealing poker for Zero Schwiefka (Robert Strauss). Although Frankie's methodical dealing skills have earned him the title "the man with the golden arm," his resolve to pursue a better life and resist the allure of drugs is strong.
After contacting Harry Lane (a character portrayed by Will Wright), a musical agent recommended by his doctor, Frankie makes plans to meet him. Donning a "borrowed" suit courtesy of Sparrow, they stop by Antek's for a drink, where they cross paths with Schwiefka. Frankie announces his intention to quit dealing, but Schwiefka retaliates by reporting him and Sparrow to the local police, leading to their brief arrest. Under pressure, Frankie is forced to acquiesce and return to his old ways, which Angers Zosch, who believes his choices are foolish.
Later that evening, Frankie seeks solace at the Safari Club, a strip bar where his former girlfriend, Molly Novotny (Kim Novak), works. Despite their lingering affection for each other, Frankie's guilt about Zosch haunts him. He urges Molly to leave her current boyfriend, Drunky John ([John Conte]), but she dismisses his concerns, revealing her own profound loneliness. A music agent named Lane offers Frankie an opportunity, yet warns him that a single lapse into addiction could end their partnership.
As the days pass without news from Lane, Frankie grows despondent. A chance encounter with Louie leads him back into the world of drugs, and amidst his struggles, his hideaway at Antek's proves to be a double-edged sword. He finds himself torn between Zosch, who urges him to deal in a high-stakes game, and Molly, who encourages him to pursue his musical dreams.
Meanwhile, complications arise when Schwiefka uses Frankie's reputation to lure in high-stakes gamblers. Increasingly desperate for cash, Frankie returns to dealing, which reignites his addiction. A confrontation with John leads to Molly ultimately leaving town, deepening Frankie's turmoil as he must choose between his old life and the dreams he once had.
With raging drug cravings and mounting pressure from unavoidable circumstances, Frankie finds himself at a decisive crossroads. As he attempts the audition he longed for, withdrawal symptoms derail his performance. Unbeknownst to him, Louie's revenge could endanger everything, even leading to tragic consequences for Zosch when she attempts to protect her secret.
In the end, with Molly’s help and a grueling battle against addiction, Frankie regains control of his life, confronting the past that has long haunted him. Ultimately, the film culminates in a poignant finale as Frankie and Molly step into an uncertain yet hopeful future, leaving their troubled past behind.
