Shenandoah (4-13, 1-7 ODAC) held a 29-15 lead after one and was up five 90 seconds prior to halftime only to see the Quakers (14-2, 7-1) score the final five points of the stanza to knot the game at 41-41 heading into the break.
GC then outscored the Hornets 29-5 in the third to pull away.
The Quakers scored the first seven points of the quarter, holding SU scoreless over 2:23, to take a lead they would not relinquish. After Olivia Callan stopped the streak with a jumper at 7:37, GC reeled off a 14-0 run that ended on a Sarah Donley 3-pointer with 3:18 left.
Guilford continued to press the action in the fourth, scoring 17 of the initial 21 points in the period to expand its lead out to 88-50 with 4:33 remaining.
Shenandoah scored 11 of the game's final 17 points to provide the final margin.
Heaven Walters led the victors with a game-high 19 points. GC had five women in double figures.
The Quakers shot 64 percent from the field to 42 for Shenandoah and had a 40-16 advantage on the glass.