He played 16 seasons in Major League Baseball (MLB) for the San Francisco Giants, Minnesota Twins, Texas Rangers, Detroit Tigers, and Chicago Cubs.

Nathan started out his baseball career as a shortstop in high school and in college for Stony Brook, but converted to a pitcher after being drafted by the Giants.

[2][3] In 2010, Nathan underwent Tommy John surgery to repair a torn ulnar collateral ligament in his throwing elbow and missed the entire season.

[7] Only Division III colleges showed minimal interest in him, and he ended up at Stony Brook University largely because his high school assistant coach Jeff Masionet and Stony Brook baseball coach Matt Senk knew each other as former teammates in the State University of New York at Cortland baseball program.

Nathan became a two-time Academic All-American and graduated as a member of the Golden Key International Honour Society.

[10] During his tenure at Stony Brook, professional baseball scouts began to notice his good arm and pitcher's body.

[7] He gave more thought to his future in baseball, however, and after graduation decided to return to the Giants organization[16] and developed into a standout pitching prospect.

After a season with the Salem-Keizer Volcanoes, he pitched for both the A and AA levels for (the San Jose Giants and Shreveport Captains) in 1998 as a starter.

[15] During his tenure with San Jose he started 22 games with an ERA of 3.32 and 118 strikeouts, leading the Class A Giants to the California League championship.

[15] Nathan was promoted to the San Francisco Giants on April 20, 1999, taking the roster spot of superstar slugger Barry Bonds, who went on the disabled list after left elbow surgery.

[21] After a short stint in the minors in 2000, Nathan spent most of the season in the majors, finishing 5–2 with a 5.21 ERA in 20 games (15 starts), and even hitting two home runs.

[20] Nathan improved slightly in 2002 to 6–12 with a 5.60 ERA in 31 games (25 starts) with Fresno,[15] but finally overcame his postsurgical struggles to return to the Giants in September with 32⁄3 scoreless innings in relief.

[26] Nathan was traded to the Minnesota Twins on November 16, 2003, along with pitchers Boof Bonser and Francisco Liriano for catcher A. J. Pierzynski and cash.

[30] He was named AL Co-Player of the Week starting on May 10 with four saves in four innings and four appearances, facing the minimum number of batters each time.

Although his record was 1–3 with a 3.57 ERA in 37 appearances, he had struck out 43 batters in 351⁄3 innings pitched, and lead the AL with 23 saves in 25 opportunities.

Felipe López singled, and Nathan was able to get Miguel Cabrera and Luis Castillo out, but not before Alou scored.

Before the 2006 season began, Nathan participated in the 2006 World Baseball Classic as one of the 30 players selected for the Team USA roster.

[41] Nathan went on to pitch the last game for the United States in the ninth inning against Mexico, again not allowing a run and striking out two.

[43] The Twins won the division on the last day of the regular season, but were swept by the Oakland Athletics in the ALDS as Nathan made one scoreless appearance.

[49] Nathan started the season with 13 consecutive saves but blew his first save of the season on May 27 by giving up a three-run inside-the-park home run on a misplayed fly ball by teammate Delmon Young; however, Nathan got two outs to end the ninth inning and the Twins went on to win the game.

[53] Nathan had a strong season, as he was selected as an All-Star for the 2009 MLB All Star Game, and he finished the year 2–2 with a 2.10 ERA and 47 saves in 52 opportunities, which was a franchise record.

However, Nathan did not fare as well in the postseason; in Game 2 of the American League Division Series against the New York Yankees, with the Twins leading 3–1 in the bottom of the ninth inning, Nathan blew the save when he surrendered a game-tying two-run home run to Alex Rodriguez.

[59] On August 10, 2011, against the Boston Red Sox, Nathan became the Twins all-time saves leader with 255, passing Rick Aguilera.

[20] He made one postseason appearance in 2014, retiring all three batters he faced in a non-save situation in Game 2 of the ALDS against the Baltimore Orioles.

During a rehab start with the Toledo Mud Hens on April 22, Nathan re-injured his elbow after throwing only 10 pitches.

He was immediately placed on the 60-day disabled list upon signing to continue recovery from his previous Tommy John surgery.

[74] He made his Cubs debut on July 24, 2016, against the Milwaukee Brewers, pitching one inning and striking out three while allowing one hit and one walk to earn the win.

[78] Nathan signed a minor league contract with an invitation to spring training with the Washington Nationals for the 2017 season.

[84] Nathan was included on the ballot for the National Baseball Hall of Fame class of 2022 when it was announced on November 22, 2021.

[91] Nathan's grandfather, Bob Brock, was a star baseball player for the Texas Longhorns and played briefly in the Boston Red Sox farm system.