The Quakers (12-1, 8-0 ODAC) clinched a bye in the upcoming six-team tournament with the win over previous co-leader SU (10-3, 7-1).
The Hornets led the game early, 2-1 following a Samantha Sisson goal at 19:09 only to see the Quakers combine a dominating performance on draws with a solid shooting performance to take total control of the contest.
E'leyna Garcia, the nation's leading scorer, knotted the game at 2-2 with a free position goal at 14:03 and in the process started a 10-goal run for her squad.
Guilford won every draw following all of the goals except the last, thus dominating possession during the run.
Garcia, who finished with a game-high eight goals, had five goals during this run including one as the halftime horn sounded.
The Quakers took a 10-2 lead into the break and stretched the lead out to nine goals, 11-2, as Garcia tallied unassisted 24 seconds into the second stanza.
Senior Corrinne Kosmowski finally snapped the SU scoreless streak with a free position goal at 28:13, but the Hornets would get no closer.
GC scored four straight following Kosmowski's goal and six of the game's final seven goals.
Amy Rollins had the final goal for the hosts.
GC outshot Shenandoah 28-15 and had 19-14 advantage in groundballs. The Quakers ended the day by taking 18 of the game's 22 draws and won 10 of 11 in the first half.
Ashley Cross had five saves for the Hornets.
SU travels to Randolph-Macon on Wednesday for a 7:00 ODAC contest.