Known during his career for his slight frame and fierce spirit of competition, Hershiser was nicknamed "Bulldog" by team manager, Tommy Lasorda.

Hershiser attended Cherry Hill High School East in Cherry Hill, New Jersey, where he was the star pitcher on the school's baseball team. He first caught the attention of pro scouts as a pitcher at Bowling Green State University in Bowling Green, Ohio; where he was a member of the Sigma Phi Epsilon social fraternity.

Hershiser was selected by the Los Angeles Dodgers in the 17th round of the 1979 amateur draft and was assigned to their farm team in Clinton, Iowa. He spent four more seasons in the minor leagues with San Antonio and Albuquerque before being called up the major leagues.

Hershiser was called up to the Los Angeles Dodgers on September 1, 1983.

He had a breakthrough season in 1985 when he led the National League in winning percentage.

His best season was 1988 when he led the league in wins (23), innings (267), and complete games (15). He finished the season with a record 59 consecutive scoreless innings pitched, breaking the mark held by Dodger great Don Drysdale.

In his final start of the year on September 28, Hershiser needed to pitch 10 shutout innings to set the mark—meaning not only that he would have to prevent the San Diego Padres from scoring, but that his own team would also need to fail to score in order to ensure extra innings. The Dodgers' anemic offense was obliging, however, and Hershiser pitched the first 10 innings of a scoreless tie, with the Padres eventually prevailing 2–1 in 16 innings. Hershiser almost did not pitch in the 10th inning, in deference to Drysdale, but was convinced by the Hall of Famer to take the mound and try to break the record.

In the 1988 National League Championship Series (between Hershiser's Dodgers and the heavily favored New York Mets, who had beaten the Dodgers 10 out of 11 times in the regular season), one of Hershiser's amazing accomplishments was recording the final out in Game 4 in relief for a save, after having started Games 1 and 3, a rarity at that time for starting pitchers.

Hershiser further pitched series-clinching Game 7 of the NLCS. He then capped the dream season in the World Series by pitching a shutout in Game 2 and the clinching victory in Game 5, winning the World Series MVP Award. He later received both the Cy Young Award and Sports Illustrated magazine's Sportsman of the Year award for his accomplishments in 1988.

After averaging over 250 innings per season from 1985–89, Hershiser suffered a career-threatening injury when he tore his rotator cuff in his pitching arm.

Hershiser returned after the injury to still be an excellent pitcher, but he never regained his level of brilliance of the late 1980s.

In 1995, he joined the Cleveland Indians, and posted a 16–6 mark to play a pivotal role in helping the team reach the World Series for the first time since 1954.

Hershiser became the most valuable player of the American League Championship Series against the Seattle Mariners. He was 14–6 for the 1997 pennant-winning Indians.

He later joined the San Francisco Giants (1998) and New York Mets (1999) before rejoining the Dodgers for a final season in 2000.

In his career, Hershiser had a 204–150 regular season record with 2,014 strikeouts and an ERA of 3.48. In retirement, Hershiser has served as a pitching coach for the Texas Rangers and then a color commentator for ESPN's coverage of baseball.