He enjoyed his best year in the Carl Yastrzemski-led 1967 Red Sox' "Impossible Dream" season, when he led American League pitchers in wins (22), games started (39), and strikeouts (246). That year, the Red Sox were involved in a four-way race for the American League pennant with the Detroit Tigers, Minnesota Twins and Chicago White Sox; the race was reduced to three teams after the White Sox lost a doubleheader to the Kansas City Athletics on September 27. The Red Sox and Twins faced each other in the season's final series and entered the final day (October 1) tied for first place; the Tigers were 1/2 game out of first and needed to sweep a doubleheader from the California Angels to force a playoff between the winner of the Red Sox-Twins game. Lonborg outdueled Twins ace Dean Chance in that finale, while the Tigers defeated the Angels in the first game but lost the second, putting the Red Sox in the World Series for the first time since 1946. In that World Series against the St. Louis Cardinals, Lonborg pitched Game Two in what was only the fourth one-hitter in Series history and followed that up with another victory in Game Five by limiting St. Louis to three hits. Called upon to pitch the seventh and deciding game with only 2 days rest, Lonborg lasted 6 innings, but allowed 6 earned runs in a 7-2 loss. In addition, he received the Cy Young Award (becoming the first pitcher in Red Sox history to win the Cy Young Award), played in the All-Star game, and finished prominently in voting for the MVP award (6th in the voting, Yastrzemski winning the award).
In December 1967, Lonborg tore the ligaments in his left knee while skiing and his pitching career thereafter was marked by many injuries. He won only 27 games from 1968 to 1971 and was traded to the Milwaukee Brewers after the 1971 season. While he performed well for Milwaukee in 1972, the team traded him in October to the Philadelphia Phillies. He spent the next six and a half seasons with Philadelphia before his release midway through the 1979 season.
In his 15-year career, Lonborg compiled a 157-137 record with 1475 strikeouts, a 3.86 ERA, 90 complete games, 15 shutouts, and 2464.1 innings in 425 games.