The Netherlands-born but Southern California-raised Blyleven became interested in baseball as a young boy watching Sandy Koufax pitch for the Los Angeles Dodgers. Blyleven was drafted by the Minnesota Twins in the third round in 1969 and after a brief stint in the minor leagues, he was called up by the Twins on June 2, 1970. In his first season, his sharp curveball helped him to ten victories and he was named AL Rookie Pitcher of the Year by The Sporting News.

However, Blyleven's early career with the Twins was not always pleasant as he was hounded by critics and fans and suffered with a dismal Minnesota Twins team. Becoming more vocal, Blyleven was traded to the Texas Rangers on June 1, 1976. He pitched well with the Rangers, throwing a 2.76 ERA in his first season and throwing a no-hitter against the California Angels on September 22, 1977, just two weeks after being sidelined with a groin injury.

On December 8, 1977, Blyleven and John Milner were traded to the Pittsburgh Pirates as part of the first four-team trade in Major League Baseball history. With the Pirates, he led the team in ERA, strikeouts and complete games in 1978 and helped them to a World Series victory in 1979.

However, Blyleven became disgruntled with the Pirates and threatened to retire during the 1980 season if he was not traded. Eventually, the Pirates did trade him to the Cleveland Indians on December 9, 1980. Blyleven sat out most of the 1982 season with an elbow injury and struggled again in 1983, but came back in 1984 with one of his best seasons: a 19-7 record with a 2.87 ERA. He missed a second 20-win season that year when he was forced to miss a couple of starts after breaking his foot when joking around in the bullpen. Blyleven was unhappy playing for the lackluster Indians and forced a trade back to the Twins, where he passed the 3,000-strikeout mark and helped the Twins to a 1987 World Series victory.

Blyleven went to the California Angels in 1989 and pitched a 2.73 ERA for a 17-5 record in his first season, but he missed the entire 1991 season following rotator cuff surgery. He came back in 1992, but was mostly unproductive, going 8-12 with a 4.74 ERA. He retired following that season with a career 287-250 record with 3,701 strikeouts and a 3.31 ERA. He tried out for the Twins again in the spring of 1993 but did not make the squad, making his retirement official (given the Twins' poor performance in that season, in retrospect this can only be considered a good thing).

In 1996, he became a color commentator for the Twins. In early 2002 during a quiet portion of a Twins game, he circled (on television) a fan carrying a sign in the stands of the Hubert H. Humphrey Metrodome, and signs reading "Circle Me, Bert" (or variants thereupon) quickly became a popular phenomenon at the Dome, continuing into all subsequent seasons to date (as of 2006).

Blyleven is often considered to be the best retired pitcher not yet in the Baseball Hall of Fame; his first year of eligibility was 1998 and if not elected, he will lose eligibility in 2012 (except by special election of the Veterans' Committee). His career stats compare equally or favorably to many pitchers currently in the Hall. Because of his long association with the club, it is believed that if elected to the Hall, Blyleven would enter as a Minnesota Twin.