The Eagles dropped to 5-15 overall and finished the first half of the league schedule with a 2-7 record. The Crusaders are now 6-14 overall and 3-6 in the PL.
Sa'eed Nelson finished with 11 points, eight assists and four steals for the Eagles, who were led on the boards by Iorio, who had five.
Jehyve Floyd hit 10 of 13 shots on his way to a game-high 23 points to lead Holy Cross, also adding six blocked shots. Caleb Green went 6-for-7 from the floor and finished with 15 points.
The Crusaders shot 60 percent (22-for-37) in the game, but the Eagles forced 19 turnovers and had 13 steals in the game.
AU, which led 25-23 at halftime, held a 55-52 lead with 5:19 left after a pair of free throws by Iorio. Holy Cross then used a six-point run, including a 3-pointer from Jacob Grandison, to pull ahead 58-55 with 2:09 to play.
Motuzis hit a pair of free throws with 1:42 left to pull the hosts within one. The deficit was three after Grandison hit two foul shots with 13 seconds left.
But a 3-pointer by AU's James Washington missed the mark with two seconds left.
Motuzis scored a dozen points in the second half, but the Eagles managed only 2 of 11 behind the arc after halftime.
American travels to Colgate in its next game on Saturday at 2 p.m. before returning to Bender Arena on Wednesday, Jan. 31 to play host to Navy.
Tickets to all American basketball games are now on sale at the Bender Arena box office or online by clicking here
For the latest on AU Men's Basketball, stay tuned to AUEagles.com and follow the team on Twitter @AU_MBasketball.