Drake took advantage to upset the 17th-ranked Bluejays 74-69 on Wednesday night.
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McDermott's teammates did erase a 16-point halftime deficit they helped create. But the Bluejays simply aren't the same without their flu-ridden superstar and they lost consecutive games for the first time this season.
Richard Carter scored 20 points and Ben Simons added 13 for the Bulldogs (9-10, 3-5 Missouri Valley Conference), who blew a 16-point lead before rallying for their first win over a ranked opponent in five years.
"They took our best shot in the second half and were still able to execute," Creighton coach Greg McDermott said.
Grant Gibbs brought Creighton within 71-69 with 32 seconds left, and the Bluejays got the ball back on a steal. But Gibbs missed an easy layup over the shorter Carter, and Simons sealed the win with two free throws with 0.5 seconds left.
"We've had a couple of rough spots so far this season. They showed great resilience and toughness to bounce back and win a big game for us," Drake coach Mark Phelps said.
Doug McDermott had 19 points to lead Creighton, which shot just 24 percent from 3-point range. But McDermott had just two points in the second half and didn't touch the ball on Creighton's last two possessions.
"He got sick at halftime. That's what happened," Greg McDermott said. "We tried to get as much out of him as we could in the second half.'
Four days after losing by three points to No. 20 Wichita State, the Bluejays opened with perhaps their worst half of the season.
Drake's substantial lead didn't last long, though.
Will Artino's dunk off an alley-oop pass preceded two layups by Gibbs that brought Creighton within 53-51 with 12:03 left. Creighton finally retook the lead, 62-61, with 7:10 to go on McDermott's only basket of the second half.
It seemed like the Bluejays would simply keep rolling behind a resurgent McDermott. But nobody but the Bluejays knew just how sick McDermott really was.
Gibbs added 18 points for the Bluejays, who outscored Drake 41-30 in the second half but couldn't get it done in the final minutes.
"We're disappointed. We expect to win every game you play," Greg McDermott said. "We as a coaching staff need to do a better job of getting our team to understand how much one possession can mean. Because essentially we lost two one-possession games."
Creighton pounded Drake by 30 points in their meeting in Omaha two weeks ago.
The Bulldogs seemed intent on returning the favor in the first half alone.
Consecutive 3s by Carter gave the Bulldogs a 25-20 lead, riling up a home gym that was much more packed than it usually is. With everyone but McDermott struggling for Creighton, Drake pushed its lead to 41-28 on a layup by Seth VanDeest.
McDermott then got called for a sloppy travel under the basket, and Chris Hines drilled a 3 from the elbow that put the Bulldogs ahead 44-28 at halftime.
It was a stunning turnaround from what happened in Omaha and what happened to Drake the last time out. The Bulldogs got pounded 85-55 by Northern Iowa just three days earlier - and responded with their first win over a ranked foe since winning at Butler in 2008.
"What we did at Northern Iowa wasn't indicative of what we can be and what kind of team we are," Simons said.
McDermott's teammates chipped in with just four baskets in opening 20 minutes. Though they worked as hard as they could to bail out their ill leader, that massive first-half hole proved fatal.
"It's an effort thing. It's a concentration thing, and it's unacceptable for us to come out and play like that," Gibbs said. "We've just got to change our attitude."