On March 7, 2019, Pedroia made his spring training debut, hitting a single in his lone at bat of the game while playing in the field for two innings; it was his first game action since May 2018. He began the season on the injured list. On April 4, he was sent to the Class A Greenville Drive on a rehabilitation assignment, where he played in three games, batting 3-for-9. Pedroia was activated for Boston's home opener on April 9, appeared in six games while batting 2-for-20 (.100/.143/.100), and returned to the injured list on April 18 due to left knee irritation. He began a rehabilitation assignment with Double-A Portland on May 2. On May 11, he was scratched from a start due to knee discomfort, and his assignment with Portland was halted on May 13. He restarted his rehabilitation, first with Triple-A Pawtucket on May 17, and then with Double-A Portland on May 24. Pedroia was removed from Portland's May 24 game due to left knee soreness.