Pantages arrived in the Yukon during the Klondike Gold Rush and recognized immediately that the real money was in entertainment, not mining. He worked as a waiter and porter at the Dawson City Opera House, saved his earnings, eventually managed the venue, and after a fire destroyed it in January 1900, helped rebuild it as the Orpheum Theatre—which opened with a night of "wine, women and song" and took in over $3,000. He moved to Seattle, opened a ten-cent vaudeville and film house called the Crystal Theater, and never stopped expanding. By the peak of his career, Pantages owned or operated 84 theaters across the United States and Canada, running tours that originated in Winnipeg and moved west through a circuit that dominated the entertainment market west of the Mississippi River throughout the 1920s.

Pantages was famous for discovering talent himself rather than relying on New York agents, and for commissioning his own architects. His preferred designer, B. Marcus Priteca of Seattle, developed an elaborate neo-classical style that Pantages called "Pantages Greek"—ornate, theatrical, and distinctly his own. The circuit expanded to include film as well as live vaudeville, partnering with Famous Players (a Paramount subsidiary) in the early 1920s. The combination of live performance and movies made his theaters uniquely attractive. When talking pictures threatened to upend the industry in the late 1920s, RKO—freshly formed by David Sarnoff and backed by Joseph P. Kennedy—approached Pantages to buy his entire chain. He turned them down.

In the midst of the Wall Street crash of October 1929, Pantages was arrested and charged with the rape of a seventeen-year-old aspiring vaudeville dancer named Eunice Pringle, who alleged he had attacked her in his downtown Los Angeles theater. William Randolph Hearst's Los Angeles Examiner covered the trial with gleeful hostility—portraying Pantages as cold, foreign, and dangerous while humanizing Pringle through family portraits and emotional outbursts in court. Pantages was convicted on October 27, 1929, and sentenced to fifty years in prison. His attorney Jerry Giesler won him a new trial on appeal, arguing the original judge had improperly excluded testimony about Pringle's history. Pantages was acquitted in the second trial in 1931.

The acquittal came too late. The trials had destroyed Pantages financially, and he sold the theater chain to RKO for considerably less than what the circuits had cost him to build—and far less than RKO had originally offered before the scandal. He retired and died in 1936, interred at Forest Lawn Memorial Park in Glendale. The rumor—first circulated during the second trial and later revived in a 1997 biography of Joseph P. Kennedy—was that RKO and Kennedy had paid Eunice Pringle to frame Pantages, to force the sale of a chain he had refused to sell voluntarily. Whether true or not, the allegation captured something real about how power worked in the entertainment industry: the acquisition of a Greek immigrant's theater empire by the forces he had once outmaneuvered.