Shenandoah (4-12, 1-6 ODAC) led for virtually the entire first half only to see Macon (9-6, 4-3) begin its comeback late in the second quarter and complete it in the third.
Sophomore Mia Moore gave the Hornets their biggest lead, seven points, thanks to a 3-pointer at the 8:26 mark of the second.
SU continued to hold the lead and had a five-point advantage as late as the 3:16 mark before the Yellow Jackets answered back.
Leading 24-19 following a Jordan Sondrol 3-pointer with 3:16 to go, the Hornets saw Macon score eight of the final 11 points of the half to knot the contest at 27-27 as the two teams headed into the halftime break.
R-MC scored the initial bucket of the third, but Shenandoah kept pace and the two teams were separated by no more than four points until the 'Jackets seized control midway through the stanza.
After an Olivia Callan layup tied the contest at 37-37 at 5:58, Macon scored 12 of the next 14 points of the game to a take a lead it would not relinquish.
Four of the 'Jackets five buckets during the run were layups.
Moore scored the final bucket of the third on a three-foot jumper 23 seconds before the horn to cut the deficit to 10, but Macon wasn't finished.
Randolph-Macon scored the first 13 points of the fourth to extend its lead to 23 points before coasting home to the 19-point victory.
Sondrol and Erin French both had 11 points for the Hornets with French posting 10 rebounds.
Moore gave SU a third woman in double figures with 10 points.
Both teams shot 45 percent from the field with R-MC grabbing 48 of the game's 72 rebounds. This 24-rebound advantage led to a 21-4 bulge in second-chance points.