Nicknamed "Boomer" for his physique (6-3, listed at 250 pounds (109 kg) but thought to be much more) and off-field interests such as Harley-Davidson motorcycles, Wells was a journeyman starter for the first eight seasons of his career. He debuted for the Toronto Blue Jays in 1987 as a reliever and did not secure a job as a full-time starter until he was 30 years old, despite pitching well most of the time.

He emerged as a top-flight pitcher in 1995, when he was 32. After starting the year at 10-3 for the last-place Detroit Tigers and making his first All-Star Game appearance, he was traded to the Cincinnati Reds for C.J. Nitkowski, Mark Lewis, and prospect Dave Tuttle. He finished that season with a 16-8 record and a 3.04 ERA. At the end of the season he was traded to the Baltimore Orioles for Curtis Goodwin and prospect Trovin Valdez. In 1996 he pitched then-career high 224 innings but finished with an 11-14 record.

In 1997, he signed as a free agent with the New York Yankees, his favorite team because of a lifelong interest in baseball legend Babe Ruth. He asked for uniform number 3, and was of course denied, as the Babe's number had been long retired. He ended up taking 33 for the Yankees. (He wore 3 for the Red Sox in 2005, before deciding to switch numbers with teammate Edgar Renteria who wore # 16 and gave Renteria his number 3 a number of which he wore when he was with the Cardinals, Wells did it to try to end a slump.) After posting a 16-10 mark in 1997, Wells pitched brilliantly in the Yankees' record-setting 1998 season. He rung up an 18-4 record, finished fifth in the league in ERA (3.49) and was third in voting for the Cy Young Award.

On May 17, 1998, Wells became the 15th pitcher in major league history to pitch a perfect game when he blanked the Minnesota Twins, 4-0. In an interesting historic note, Wells attended the same San Diego high school as Don Larsen, whose perfect game for the Yankees in the 1956 World Series remains the only no-hitter ever thrown in postseason play and was until then the only perfect game thrown by a Yankee. David Cone would add a third Yankee perfect game in 1999.

After the season, Wells returned to the Blue Jays as part of a trade for Roger Clemens, along with Homer Bush and Graeme Lloyd. He continued to win north of the border, with records of 17-10 and 20-8 over the next two years. He and pitcher Matt DeWitt were then traded to the Chicago White Sox, in a deal that was quickly mired in controversy. The primary player being traded by the White Sox, starting pitcher Mike Sirotka, was injured at the time of the deal, and he never pitched in the major leagues again. Toronto's general manager, Gord Ash, had not made the deal contingent on the results of a medical examination, however, and MLB ruled in favor of the White Sox. The Blue Jays thus received only Kevin Beirne, Brian Simmons, and minor leaguer Mike Williams, and the mistake ultimately cost Ash his job.

The deal did not turn out particularly well for the White Sox, either, as Wells struggled with back problems in 2001 and pitched only 100 2/3 innings. After the season's end, he returned to the Yankees, a deal that was again immersed in controversy as he had already reached an oral agreement to join the Arizona Diamondbacks. Despite having lost some velocity from his fastball, he retained his excellent curveball and his control, and posted an outstanding 19-7 record in 2002.

Wells was the subject of some controversy prior to the 2003 season, when his autobiography Perfect I'm Not: Boomer on Beer, Brawls, Backaches and Baseball, was published. The book upset the Yankees' management, and Wells was fined $100,000 by the team for disparaging comments which appeared in it. Amusingly, Wells claimed to have been misquoted in the book, which was presumably penned by a ghost writer. The problems didn't carry over to the field, however. Wells posted a 15-7 record and helped the Yankees win another pennant.

On September 28, 2003, the final day of the regular season, Wells earned the 200th win of his career in a game managed by Clemens, who had won his 300th game earlier in the season and was thought to be retiring from baseball (Clemens ended up putting off his retirement). Regular Yankees manager Joe Torre let Clemens manage the last, meaningless game of the regular season, and Clemens pulled Wells from the game in the eighth inning.

On January 1, 2004, Wells was signed as a free agent by the San Diego Padres to a one-year contract. Wells posted a 12-8 record with a 3.73 ERA to start off his second stint in the National League.

On December 11, 2004, Wells signed a two-year deal with the Boston Red Sox. Getting off to a bad start, many fans questioned the decision of general manager Theo Epstein, but after coming off of the DL and getting rocked in his first start back in Oakland, David Wells became the same dominating pitcher he was in the past. He went on to post a 15-7 record, with a 4.45 ERA. Wells pitched much better than his ERA may show, but had a few very poor outings, which caused his ERA to "balloon." After the 2005 season, Wells requested a trade back to the West Coast, but he eventually withdrew that request and has resigned himself to one last year pitching for the Red Sox, after which he is expected to retire.

On March 28, 2006, the Red Sox announced that Wells would begin 2006 on the disabled list, as he is still recovering from surgery performed on his right knee. In Wells' absence, the Red Sox have relied upon a four-man pitching rotation, featuring Curt Schilling, Tim Wakefield, Josh Beckett, and Matt Clement. After pitching one game on April 12, he was once again placed on the 15-day disabled list. He has announced that if his knee does not improve he will retire.

Wells owns a career record of 227-143, including a 164-90 mark since 1995. His career ERA of 4.06 looks unimpressive, but it is above average for the big-hitting era in which he's had his best seasons.

Actuary Jon Ketzner once said Wells has "the best body in baseball." He is widely considered to have been joking - but Wells' longevity is nonetheless quite notable.

David Wells is the uncle (by marriage) of Toronto Blue Jays outfielder Vernon Wells.