Bob Knepper's journey in Major League Baseball began when he was drafted by the San Francisco Giants in the second round of the 1972 MLB Draft. A left-handed pitcher, Knepper made his debut with the Giants on September 10, 1976. Over the next few years, he established himself as a reliable starting pitcher for the team. His rookie season in 1977 saw him posting a 11-9 record with a 3.36 ERA, setting the stage for a solid career.

Knepper's tenure with the Giants lasted until 1980. During this period, he developed a reputation for his effective pitching style, which relied on control and movement rather than overpowering velocity. In 1978, he had one of his best seasons with the Giants, achieving a 17-11 record and a 2.63 ERA, which ranked among the best in the National League. His performance earned him a spot in the All-Star Game that year, marking his first appearance in the midsummer classic.

In December 1980, Knepper was traded to the Houston Astros, a move that would define the next significant phase of his career. With the Astros, Knepper continued to be a dependable starter, contributing to the team's success throughout the 1980s. His first season with Houston in 1981 was shortened by a players' strike, but he still managed to post a 9-5 record with a 2.18 ERA, helping the Astros reach the postseason.

Knepper's most remarkable season came in 1986 when he played a crucial role in the Astros' run to the National League Championship Series. That year, he recorded a 17-12 record with a 3.14 ERA and was selected for his second All-Star Game. The Astros faced the New York Mets in a memorable NLCS, which went to a dramatic Game 6. Knepper started that game and pitched well, but the Astros ultimately lost in a 16-inning thriller, ending their World Series hopes.

Throughout his career, Knepper was known for his durability and consistency on the mound. He was a workhorse for the Astros, regularly pitching over 200 innings in a season. His ability to pitch deep into games was a valuable asset for the team, and he often served as a mentor to younger pitchers.

In 1989, Knepper returned to the San Francisco Giants, the team where his major league career began. He pitched for the Giants during the 1989 and 1990 seasons, providing veteran leadership and experience to the pitching staff. Knepper retired from professional baseball after the 1990 season, concluding a career that spanned 15 years in the major leagues.

Over the course of his career, Bob Knepper compiled a 146-155 win-loss record with a 3.68 ERA and 1,473 strikeouts.