The Bishops (11-10, 8-8 USA South) had not won in Winchester over the Hornets (9-13, 6-9) since January 19, 2002, but finished off the season sweep over SU with the 11-point victory Saturday afternoon.
Shenandoah scored eight of the game's first 10 points, but went cold from the field midway through the first half in allowing N.C. Wesleyan back in it.
Leading 8-2 at the 17:19 mark, the Hornets saw NCWC go on an 8-2 run of its own to tie the contest at 10-10 with 12:46 remaining.
The two teams split the next six points before Wesleyan took a lead it would not relinquish on the strength of a 12-4 run over a span of 4:59.
Shenandoah went cold from the field in the final 9:22, missing 10 of 11 shots from the field with the only successful attempt coming on a Gabielle Clarke layup at the 7:39 mark.
NCWC answered that Clarke layup with a 17-5 run to finish the half and took a 37-22 lead into the lockerroom.
The Bishops eventually expanded this advantage out to 19 points before SU awakened with a 12-0 spurt from the 16:35 to 11:31 marks that cut the deficit to seven points.
Unfortunately for the Shingleton Gymnasium crowd, this would prove to be the hosts' high-water mark.
NC Wesleyan answered the Shenandoah run with a 6-1 run of its own and never let it lead dip below nine points the rest of the way.
Tiffany Bell paced the victors with 12 points while Samantha Urquhart adding 11.
Kerby Hatter had 10 points for the Hornets.
SU hosts Meredith on Sunday at 2:00 in a Senior Day contest.