Shenandoah (5-8, 2-4 USA South) had an 18-point second half lead on the Bishops (6-6, 3-4) only to see NCWC roar back for the victory.
The Hornets headed into the game on a 14-game winning streak over Wesleyan and hadn't lost since NCWC won 55-54 on a last-second bucket on January 15, 2005.
It appeared Shenandoah was on its way to another victory in the long-time series after junior Nicole Gilbertson hit a layup to give SU a 48-30 lead with 14:09 remaining.
But the Bishops had other ideas.
The hosts scored 21 of the game's next 24 points, including the first 12 straight, in a span of 10:15 to tie the contest at 51-51 with 3:35 remaining.
After Tiffany Bell knotted matters at 51-51 with a free throw, N.C. Wesleyan continued its run by scoring another four straight points to lead 55-51 with 2:19 left.
Shenandoah, thanks to a Gilbertson free throw and a Mandy Johnson 3-pointer, tied it at 55-55 by the 1:18 mark, but Wesleyan pulled away with four straight points and sealed the victory.
The Hornets had taken a 34-23 lead into the halftime lockerroom thanks to 39 percent (11 of 28) shooting in the first half, but were held to just 19 percent (6 of 31) after the break.
SU also hit five of its six 3-pointers in the first half.
Gilbertson led the Hornets with 14 points while Kerby Hatter added 12 and Johnston 11.
Shelby Jackson had 10 for NCWC.
Shenandoah continues this roadtrip with a 2:00 contest at Meredith Sunday afternoon.