Two days after Nicholas' running three-pointer at the buzzer pushed Maryland (21-9) past North Carolina-Wilmington, the Terrapins dominated and built a 45-28 lead at halftime.
Ryan Randle scored 11 points and hounded Xavier All-American David West into two-of-eight performance from the field.
"I thought today we played better, because of the edge of the competition," Maryland Coach Gary Williams said. "We felt comfortable out there today because we just played Friday."
West fought back in the second half as Xavier (26-6) gradually chipped away. Romain Sato split a pair of free throws to pull the Musketeers within 60-57 with just over six minutes remaining.
Nicholas helped put an end to Xavier's momentum by making a badly needed three-pointer from the top of the key on Maryland's next possesion.
"It was huge," Maryland guard Steve Blake said. "They were making a great run at us, putting us on our heels. Drew came up and gave us a lot of confidence with that shot."
After a layup by the Musketeers' Anthony Myles, Blake hit a jumper and Jamar Smith dunked for an eight-point lead with nearly 4 1/2 minutes to go.
The Terrapins are in the Sweet 16 for the fifth time in six years and 13th time overall and are 13-1 in the last three NCAA Tournaments.
"Until we get beat, we're going to be the defending national champions," Terrapins forward Tahj Holden said. "We have a lot of experience and we use it to our advantage."
Randle and Nicholas each scored 17 points for Maryland, which shot 52 percent, the 13th time this season it topped 50 percent. Nicholas grabbed eight rebounds as the Terrapins held a 39-28 edge on the glass.
Smith came off the bench and supplied plenty of energy, making all six shots for 12 points. The Terrapins' reserves scored 23 points.
"He was incredible," Williams said. "Jamar's had some outstanding games and some games where he can't do it at that level. The second half especially, Jamar was very important to us."
Xavier, on the other hand, used just seven players and guards Sato and Lionel Chalmers each played the entire game. West, a three-time Atlantic 10 Player of the Year, finished with 22 points and nine rebounds in his final game.
"In the first half, the shots were going in and out," West said. "In the second half, I really had no problems scoring. It's tough, not playing another college game."
The Musketeers scored the game's first five points before the Terrapins seized command. A dunk by Randle triggered 13 straight points that gave Maryland a 21-9 lead after Smith dunked with 10:39 to go in the half.
Freshman Travis Garrison's layup gave Maryland its largest lead at 43-25 and it settled for a 17-point bulge at intermission. The Terrapins held a 28-8 advantage in points in the paint over the first 20 minutes and had 12 layups to just one for the Musketeers.
"We just couldn't get into the fow of the game," Xavier Coach Thad Matta said. "Against a team like Maryland, you have to be clicking every second of the game."