Buehler made his first major league start on April 23, 2018, against the Miami Marlins, pitching five scoreless innings. On May 4, against the San Diego Padres, he took a no-hitter through six innings, with eight strikeouts, until being taken out of the game after 93 pitches. Three relief pitchers combined to finish it off as the Dodgers won 4–0, the first combined no-hitter in franchise history. He was placed on the disabled list on June 21 because of a rib injury. He returned to make an appearance out of the bullpen on June 28 but allowed five earned runs in one inning before returning to the disabled list. On July 13, Buehler made his first start in over a month against the Los Angeles Angels, allowing two solo home runs to Kole Calhoun but no other earned runs. He set a new career high in strikeouts with nine on August 22. After three more nine-strikeout starts, he struck out 12 on September 19 against the Colorado Rockies.
On October 1, Buehler started the NL West Tie-Breaker Game against the Colorado Rockies. He picked up the win, giving up only one hit and allowing no runner to advance past second base. He also got his first career MLB run batted in in his 47th plate appearance. In 24 appearances for the Dodgers (23 starts and one relief appearance) in 2018, Buehler was 8–5 with a 2.62 ERA and 151 strikeouts. In the 2018 NLDS against the Atlanta Braves, he started one game and allowed five runs in five innings; in the 2018 NLCS against the Milwaukee Brewers he started two games, allowing five runs in 11⁄3 innings; and he threw seven scoreless innings in Game 3 of the 2018 World Series against the Boston Red Sox. Buehler finished third in voting for the National League Rookie of the Year, behind Atlanta Braves outfielder Ronald Acuña Jr. and Washington Nationals outfielder Juan Soto.