With Shenandoah (8-5, 3-3 ODAC) leading 5-2 following an Orlando Levins-to-Stephen LaTona goal 90 seconds into the second quarter, Roanoke (9-3, 5-1) scored six straight to take an 8-5 lead into the half.
Michael Brooks scored unassisted for the Hornets at the 13:39 mark of the third, but once again the Maroons had an answer.
Roanoke outscored SU 6-3 to finish the third and take a 14-9 lead heading into the final 15 minutes.
He breaks the record previously held by Chris Keller '03.
Sanders, who had five assists on the night, wasn't done breaking records, however.
His final assist, setting up LaTona with 11:16 remaining, was his 41st of the season and breaks the record he set in 2015.
LaTona's goal, one of three on the night for the senior, gives him a season-record tying 46 this year. His next goal breaks the mark he now co-holds with Justin Ratcliff '07.
Roanoke outshot SU 59-37, won 20-of-34 faceoffs and had a 50-30 advantage in groundballs.
Goalkeeper Ben Judy had 10 saves.
"While we didn't get the result we wanted tonight I am very proud of the effort," head coach Tim Marshall said. "Congrats to senior Tilghman Sanders on breaking the all-time assist record and breaking his own single season record. He makes everyone around him better."