The Angels prospect, who has four homers this season with Class A Cedar Rapids, swatted the final pitch he saw over the center-field fence at Modern Woodmen Park, giving him enough points in the final round (52) to best Fort Wayne's Jake Blackwood, who finished with 49.
Witherspoon's last hit was worth twice as many points in the Derby's scoring system.
Lansing's Marcus Knecht and Bowling Green's Derek Dietrich each advanced past the first round representing the Eastern All-Stars, while Peoria's Greg Rohan and Beloit's Dan Ortiz hit their way into the second round from the West.
Blackwood's best performance came in the second round, when he totaled 109 points. Witherspoon had 62 points in the round, enough to send him to the finals. Quad Cities did not release final statistics for home runs hit.
Fans can get another look at both sluggers tomorrow, when the River Bandits host the Midwest League All-Star Game at 6 p.m. ET.