From 2000 to 2004, Foulke was one of the top closers in baseball. At the peak of his career, he had an effective 87-89 MPH fastball and what many people considered to be one of the best circle changeups in the sport (which he could get down to 76 MPH, making for a 12-14 MPH difference in the two, a sign of a good changeup.) However, later in his career, his fastball ranged from 84-86 MPH while his changeup remained at 76 MPH. While solid against right-handed hitters, he is particularly lethal against lefties. His strikeout pitch is usually an inside circle changeup.

After graduating from Hargrave High School in Huffman, Texas in 1991, Keith Foulke attended Galveston College and Lewis-Clark State College in Idaho. He began his career in the minor-league system of the San Francisco Giants, but was traded to the Chicago White Sox in 1997 with five other prospects for starting pitchers Wilson Álvarez and Danny Darwin, and top reliever Roberto Hernández in the infamous White Flag Trade.

In 1998, Foulke found a home in the White Sox bullpen, primarily serving as set-up man for closers Matt Karchner (who was traded to the Chicago Cubs in the middle of the season) and Bill Simas. In 1999, Foulke established himself as one of the league's best relief pitchers, posting a 2.22 ERA in 105.1 innings of work over 67 games, however, he was still used primarily as a set-up man. His stellar season even netted him a vote for the 1999 AL Cy Young Award.

In 2000, Foulke again was an important piece of the White Sox bullpen. Though Bob Howry entered the season as the team's primary closer, Foulke was seeing more and more time closing out games, and by April's end he had recorded 4 saves (in 1999, he didn't notch a save until June). As Howry continued to struggle, Foulke inherited the closer's role and flourished, saving 34 games for the White Sox in 2000, and was a major reason the White Sox won the AL Central title.

On December 3, 2002, Foulke, along with catcher Mark Johnson, minor league pitcher Joe Valentine, and cash, was traded by the White Sox to the Oakland Athletics for closer Billy Koch and two minor leaguers. During the 2003 season with the Athletics, Foulke would distinguish himself as a closer, leading the league in saves and games finished, being named to the All-Star team and winning the American League Rolaids Relief Man of the Year Award. However, it was Foulke who also gave up the game-winning double to David Ortiz in Game 4 of the American League Division Series that year.

Foulke was granted free agency on October 27, 2003, and signed with the Boston Red Sox. Foulke continued his dominance in his first year with the Red Sox, saving 32 games in 39 opportunities while racking up 79 strikeouts and a 2.17 ERA across 83 innings. In the 2004 postseason, Foulke appeared in 11 of 14 games, throwing 257 pitches over 14 innings. He would rack up 19 strikeouts and over the entire stretch would only allow exactly one earned run. Foulke was on the mound when the final out was made in the 2004 World Series. He induced Edgar Rentería of the St. Louis Cardinals to hit a one-bounce ground ball back to him which he flipped to first, thus clinching the Red Sox' first World Series Championship since 1918.

Despite being the hero of the previous postseason, Foulke struggled to keep his job as closer as he battled knee injuries throughout 2005. His ERA ballooned to over 5.00 and he eventually lost the role of closer to Mike Timlin. On June 28, 2005, after struggling with injuries and a 6.03 ERA to that point, Foulke lashed out at Red Sox fans, who were booing him.  "They're not going to make it any harder than it is for me to go home and look in the mirror", Foulke said about the booing that rained down from the stands on a sticky night in the Fens. "Like I've told you guys plenty of times, I'm more embarrassed to walk into this locker room and look at the faces of my teammates than I am to walk out and see Johnny from Burger King booing me. I'm worried about these guys, not everybody else."

Foulke's perceived lack of respect for Red Sox fans made him a target for both fans and the Boston media alike. His baseball heart was also questioned because he said he did not care if he was a closer, but clarified, "I love to pitch. I don't care if I pitch in the second inning, the fourth inning, the ninth inning, the 10th inning. I didn't ask to be a closer. It's just the job that I do." The media also had a field day when they found out that Foulke demanded a new truck as compensation for his weekly interviews on WEEI.

The Red Sox had high expectations for Foulke in 2006, after two knee surgeries in the offseason. Manager Terry Francona was hoping to put Foulke back in the closer role, but after an inconsistent spring and early regular season games, Francona was quick to go to Jonathan Papelbon as the closer. Foulke pitched mainly as one of the team's middle relievers, along with Mike Timlin, Julián Tavárez, and Rudy Seánez. Foulke continued to struggle, with an ERA of 5.63. On June 12, 2006, Foulke was put on the disabled list with right elbow tendinitis. Foulke was activated from the 15-day DL on August 18. In November 2006, Foulke opted for free agency.

Foulke signed a one-year deal (with an option for a second year) with the Cleveland Indians for the 2007 season after passing a physical in January. However, Foulke announced his retirement on February 16, 2007, before ever putting on an Indians uniform. He cited pains in his elbow and injuries from the previous two seasons as the primary reason for ending his ten-year career.

On February 8, 2008, Foulke returned from retirement and signed a one-year contract with the Oakland Athletics, for whom he had previously closed in 2003. Foulke played for the Newark Bears in the Atlantic League of Professional Baseball.