Ryan was taught to play baseball by an elder brother and was a wild but fast pitcher in high school before he was signed by the National League New York Mets in 1965. He pitched for their minor league teams (1965–67), and, except for time out for military service, he pitched regularly for the Mets through the 1971 season and was then traded to the American League California Angels. Although he pitched brilliantly in relief for the Mets in 1969 when they won the pennant and the World Series, he came into his own as a pitcher with the Angels, leading the league in strikeouts seven of his first eight years with them (1972–74, 1976, 1977–79). In 1980 he moved as a free agent to the National League Houston Astros, and he moved to the Texas Rangers in 1989.

The extraordinarily durable Ryan was still a leading pitcher in his early 40s. In 1989 he struck out his 5,000th batter; he also held the record for most strikeouts in a season (383 in 1973). He led the American League in strikeouts a total of 10 times and was the oldest pitcher ever to lead a league in strikeouts (in 1989 at age 42). In 1991 Ryan, who was nicknamed the “Ryan Express,” pitched his seventh no-hit game, establishing another record. He also held the major league record for most games with 15 or more strikeouts in a career (26). In 1993 Ryan retired from baseball, and in 1999 he was inducted into the Baseball Hall of Fame. At the end of his 27-year career in the major leagues, Ryan finished with 324 wins and 292 losses and an earned-run average of 3.19; he also finished fifth in innings pitched (5,386) and tied with former Mets teammate Tom Seaver (Seaver, Tom) for seventh all-time in shutouts (61).

Following his retirement from playing, Ryan continued to be active in the sport, including having an ownership interest in two minor league teams and serving as a consultant to the Houston Astros. In 2008 he became team president for the Texas Rangers.

Ryan wrote several autobiographies, including Throwing Heat: The Autobiography of Nolan Ryan (1988), written with Harvey Frommer; Miracle Man: Nolan Ryan, the Autobiography (1992), written with Jerry Jenkins; and Nolan Ryan: The Road to Cooperstown (1999), written with T.R. Sullivan and Mickey Herskowitz. He also collaborated on instructional guides, such as Pitching & Hitting (1977) and Nolan Ryan's Pitching Bible (1991).