Wetteland was signed by the Dodgers as their second choice in the June 1985 amateur draft. He was later claimed by the Detroit Tigers in December 1987 as a Rule 5 draft, but was soon returned to the Dodgers. While playing in the Pacific Coast League, he made notice by earning 20 saves in 20 chances. He made his major league debut on May 31, 1989. After struggling with his first five starts in 1991, Wetteland asked to be switched to the bullpen, and became a full-time closer in 1992.

After the 1991 season, Wetteland was traded twice; first to the Cincinnati Reds for Eric Davis, and then to the Expos for Dave Martinez. On April 5, 1995 he was traded to the Yankees for Fernando Seguignol.

During the 1996 season, he led the American League in saves, with 43, and appeared in the All-Star Game. Wetteland was given the World Series MVP Award that year, when he led the Yankees to the World Championship. His four saves during the Series ties the record for the most saves in a single postseason series, and his seven saves in the full postseason were the most ever. He was awarded with the 1996 Rolaids Relief Man Award.

He was signed by the Texas Rangers as a free agent on December 16, 1996, signing a 4-year contract worth $23 million. Before the 1999 season, Wetteland underwent elbow surgery. Although this robbed him of some of his fastball speed, it allowed him to expand his repertoire to include a slider, curveball, and change-up. Wetteland was again named to the All-Star game for the 1999 season, where he pitched a scoreless 9th inning, and became the first Rangers pitcher to earn an All-Star save. His 43 saves that year set a new Rangers record. His final game was on September 20, 2000, and he retired after his Rangers contract expired during the 2000 offseason.

Wetteland was awarded the Rolaids Reliever of the Decade, and earned the most saves of any pitcher during the 1990s, and the Rangers all-time saves leader. He is tied with Dennis Eckersley for the most seasons with over 40 saves. His final win/loss percentage was .516, with 48 wins and 45 losses.

In 2005, Wetteland was inducted into the Texas Rangers Hall of Fame.

In 2006, his first year of eligibility, Wetteland received less than 5f the vote (he received 4 votes; the threshold was 26) from the Baseball Writers Association of America (BBWAA) for induction into the Baseball Hall of Fame, thus becoming ineligible to appear on future BBWAA ballots. However, he may eventually be considered for induction into the Hall by the Veterans Committee once 20 years have passed from his date of retirement (therefore, in the year 2021), in accordance with current Hall of Fame rules (enacted in 2001).

Wetteland, a born-again Christian, met his wife, Michele, while playing for the AA San Antonio Missions. They, along with their four children, live in Texas. He was known for wearing the same baseball cap throughout the entire season.

On January 27, 2006, John was hired to be the bullpen coach of the Washington Nationals.