Bob Lillis embarked on his professional baseball journey as a player and later transitioned into coaching and managing roles. His career began when he was signed by the Brooklyn Dodgers as an amateur free agent in 1951. However, it wasn't until 1958 that he made his Major League Baseball debut with the St. Louis Cardinals. Lillis played as an infielder, primarily at shortstop, and was known for his defensive skills on the field.

After his stint with the Cardinals, Lillis was traded to the Los Angeles Dodgers in 1961. During his time with the Dodgers, he contributed to the team's depth in the infield, although he was often utilized in a backup role. His tenure with the Dodgers lasted until 1963, after which he was selected by the Houston Colt .45s in the expansion draft. The Colt .45s, who later became the Houston Astros, provided Lillis with more playing opportunities, and he became a regular fixture in their lineup.

Lillis played with the Houston team until 1967, marking the end of his playing career. Over the course of his playing days, he was recognized for his steady glove work and ability to fill in at various infield positions. While his offensive numbers were modest, his defensive reliability made him a valuable asset to his teams.

Following his retirement as a player, Lillis transitioned into coaching and management. He joined the Houston Astros' coaching staff, where he served in various capacities, including as a bench coach and infield instructor. His understanding of the game and ability to mentor younger players were assets that he brought to the coaching realm.

In 1982, Lillis was appointed as the manager of the Houston Astros. During his managerial tenure, he guided the team through several seasons, focusing on developing the team's young talent and maintaining competitive play. Lillis managed the Astros until 1985, after which he continued to be involved in baseball in various coaching roles.