Villanova is No. 1 in the AP Top 25 for the first time in school history. Its stay at the summit would likely be short-lived if the Wildcats become DePaul's next upset victim.
The Blue Demons, though, have lost 16 in a row to top-ranked teams, a streak the Wildcats can extend in Tuesday night's road matchup with Daniel Ochefu possibly returning.
Villanova ascended to No. 1 after a 72-60 win over then-No. 11 Providence on Saturday, which avenged its only Big East loss, and Oklahoma's 80-69 defeat at Kansas State.
"We're honored and humbled to have been voted No. 1," coach Jay Wright said. "There's still a lot of basketball left to be played and handling this will be another challenge for our team. We look forward to it."
Darryl Reynolds had a career-high 19 points on 9-of-10 shooting and 10 rebounds in the Wildcats' sixth consecutive road win and third in a row overall. The junior forward, averaging 3.0 points and 4.7 rebounds, has started the past four games with Ochefu out because of a violation of team rules and a concussion.
Ochefu, averaging 9.7 points and a team-best 8.3 rebounds, tweeted Monday that he has been cleared to return but it's uncertain if that will happen Tuesday.
His presence could go a long way toward helping Villanova (20-3, 10-1) avoid becoming the second straight ranked team to lose at DePaul. The Blue Demons (8-15, 2-9) topped the Friars 77-70 last Tuesday.
They also beat then-No. 20 George Washington 82-61 on Dec. 22 and won 57-56 at Marquette on Jan. 20.
"It goes without saying that when you create national attention and draw attention to yourself - particularly when it's this positive - that you can build on it," coach Dave Leitao said. "We're doing two things right now: We're trying to coach the heck out of a team and we're trying to build a program."
The Blue Demons' Myke Henry, averaging 15.0 points, scored 27 and added 11 rebounds against Providence. He had 22 points and eight boards at Creighton on Saturday, but DePaul was blown out 88-66.
Second-leading scorer Billy Garrett Jr. (13.2 ppg) had no points for the second time in his career while going 0 for 2 from the floor. He totaled 34 in his previous two games, both against ranked teams.
The Blue Demons are 3-18 all-time against No. 1 opponents and haven't beaten one since Dec. 27, 1952.
Villanova has won 10 straight over DePaul and taken the last six meetings by an average of 20.0 points.
Ryan Arcidiacono led the way with 18 points in the most recent, a 68-55 road victory Jan. 31, 2015. The senior guard has averaged 16.6 points and 60.9 percent shooting in five lifetime matchups, going 17 of 31 from 3-point range.
Arcidiacono has averaged 18.3 points and 60.7 percent from the floor while hitting 11 of 19 from beyond the arc in three games at DePaul. The Wildcats have won five straight there.
Henry has managed nine total points in his two contests against Villanova.