The victory clinched the third seed in the Patriot League tournament for the Crusaders (18-11, 12-5), hosts to Boston University on Saturday in their regular-season finale.
The Greyhounds (10-18, 5-12) led 30-27 at halftime after shooting 57.1 percent, but managed only 30.8 percent in the second half. Their game percentage of 42.6 was better than Holy Cross at 36.7, but the Crusaders made five more 3-pointers and scored 10 points off turnovers while outrebounding the Greyhounds 36-27. They also hit 21 of 25 free throws to Loyola's 9 of 18.
Holy Cross took the lead for good with 11:44 left in the game and gradually pulled away.
Loyola's Franz Rassman scored a career-high 15 points. R.J. Williams added 13.