Brandon Holcomb and Cameron Jones added 14 points apiece for the Highlanders (8-6), who beat the Knights 119-69 last year and came up seven points short of the 39-year old school record of 130.
Andre Battle had 17 points and Johnny Rhodes 16 for Central Penn (13-7) from the United States Collegiate Athletic Association. It was the Knights' fifth loss to a Division I opponent, and Radford has won 39 straight against lower-level teams.
Radford, which had all 13 players score at least four points, shot 60 percent. The Highlanders had a 65-25 rebounding advantage with Christian Lutete grabbing a career-high 17 and Ed Polite Jr. 11.
The Highlanders' 66 points in the second half tied a Dedmon Center record for a half.