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Chan moved with his family in 1962 from Guangzhou to Hong Kong, then in 1968 to Phoenix, Arizona and later in 1973 to Houston, Texas where his family owned restaurants. He was going to continue in the family business, but when he was 16 he went on a junket to Las Vegas, Nevada. When he was 21, Chan dropped out of the University of Houston, where he was majoring in hotel and restaurant management, and moved to Las Vegas to become a professional gambler.

Chan attributes some of his early success to the fact that many players had not previously played against Asian players. He shot to fame in the late 1980s, winning the championship event of the World Series of Poker (WSOP) in two consecutive years (1987 and 1988). A videotape of the 1988 WSOP final heads up match is featured in the movie Rounders, in which Johnny Chan makes a cameo appearance. He almost won a third consecutive title, but finished in 2nd place in 1989 to Phil Hellmuth. He is the last player to win back-to-back WSOP Main Events, a feat many prognosticators think he could hold forever given the increasingly larger fields. Jerry Buss, an avid poker player and owner of the Los Angeles Lakers, promised Chan an NBA championship ring if he could win three in a row.

Chan is known for keeping a "lucky" orange in front of him on the table, and after the second consecutive WSOP title other players began bringing fruit to the table in hopes of increasing their luck. Chan says he only had an orange with him because of the pleasant scent, as smoking, which was allowed in many tournaments then, bothered him. Chan was once a smoker, but now he neither smokes nor drinks alcohol.

In 2005, Chan won his tenth World Series of Poker title, defeating Phil Laak in a Texas hold 'em event. He is tied with Doyle Brunson for second place with 10 World Series of Poker bracelets, behind Phil Hellmuth (11). He was inducted into the Poker Hall of Fame in 2002.