On September 14, 2008, Sproles became just the second player in NFL history with 50 rushing yards, 50 receiving yards, and 100 return yards in one game (the other being Gale Sayers with the Chicago Bears). His statistics for the game included: 53 rushing yards, 72 receiving yards, and 192 return yards. Sproles logged 317 all-purpose yards in a 39-38 loss to the Denver Broncos. He also had a 103-yard touchdown return. On December 4, he had three receptions for 34 yards and two touchdowns in a 34–7 victory over the Oakland Raiders. In the regular season finale, in the second divisional game against the Denver Broncos, he had 115 rushing yards and his lone rushing touchdown of the regular season. Overall, he finished the 2008 season with 330 rushing yards, one rushing touchdown, and 29 receptions for 342 receiving yards and five receiving touchdowns. On special teams, he had 53 kick returns for 1,376 net yards and a touchdown to go along with 22 punt returns for 249 net yards.