On May 27, 2008, Byrnes was placed on the 15-day disabled list for the 1st time in his career with sore hamstrings. Byrnes underwent an MRI that showed he had tears in both of his hamstrings. Byrnes returned to the team on June 23, 2008, batting leadoff against the Boston Red Sox at Fenway Park. At the end of the 2008 season, Byrnes batted .209 with 13 doubles, 1 triple, 6 home runs, 24 RBI, and 4 stolen bases in 52 games.