He played 12 seasons in Major League Baseball, from 1991 through 2002, for the Minnesota Twins, New York Yankees, and Kansas City Royals.

Knoblauch won the American League Rookie of the Year award and a World Series ring as a member of the 1991 Minnesota Twins.

The Twins traded Knoblauch to the New York Yankees for Eric Milton, Cristian Guzmán, Brian Buchanan, Danny Mota, and $3 million on February 6, 1998.

Buster Olney, then with The New York Times, predicted that Knoblauch and Derek Jeter would form the greatest double play combination in history.

[10] Though he struggled early on with the team, he hit a career-high 17 home runs as the Yankees won a then-American league-record 114 games.

In game 2 of the 1998 American League Championship Series against the Cleveland Indians, Knoblauch was involved in an infamous defensive play.

In the 12th inning with the score tied 1–1, Indians batter Travis Fryman bunted, and Knoblauch covered first base for a possible putout.

Towards the end of his career, Knoblauch's performance at the plate grew worse, with many observers believing he was preoccupied by his fielding troubles and trying too hard to hit home runs.

Knoblauch was benched in the final game of the 2001 World Series (he hit just .056), and left for Kansas City as a free agent in the off season.

Knoblauch played in just 80 games in left field for the Royals, batting .210, and the team declined to offer him a new contract the following year.

In 2000, he began to have difficulty making accurate throws to first base, a condition sometimes referred to in baseball as the "yips" or "Steve Sax syndrome" in more recent years.

[11] After making three throwing errors in six innings of the Yankees' 12–3 loss to the Chicago White Sox, on June 15, 2000, Knoblauch voluntarily left the game.

On September 25, 2009, an officer from the Memorial Villages Police Department, near Houston, was told by Knoblauch's wife that he hit and choked her.

In the Mitchell report, Brian McNamee stated that he procured human growth hormone (HGH) from Kirk Radomski for Knoblauch in 2001 when he served as the New York Yankees assistant strength coach.