Rose accepted a scholarship to play for the University of Memphis Tigers under John Calipari, who recruited him after seeing him play in an AAU game.Strong efforts were made by Indiana University and in-state University of Illinois to sign Rose to their own programs.Illinois in particular planned to pair Rose and their five-star recruit Eric Gordon, who had played AAU basketball with Rose.Gordon, however, retracted his verbal commitment from the Fighting Illini, opting to play for Indiana, and Rose subsequently gave his verbal commitment before the start of his senior season.Rose chose Memphis because of the school's history of putting players in the NBA and the prospect of Rod Strickland, a 17-year veteran of the league, mentoring him. Rose switched to #23, due to the fact that #25 had been retired by the school in honor of Penny Hardaway.
With the addition of Rose and led by veteran upperclassmen Joey Dorsey and Chris Douglas-Roberts, the Tigers started out the season ranked third in the nation. Memphis sprinted to a 26–0 start and claimed the number one ranking in the country for the first time in over 25 years before falling to the University of Tennessee Volunteers 66–62 in February.Memphis was able to bounce back and capture the Conference USA Tournament to qualify for the "Big Dance" with a 33–1 record.Rose averaged 14.9 points per game, 4.7 assists and 4.5 rebounds per game during the regular season and earned All-American Third Team honors among others.He finished as a finalist for the Bob Cousy Award as well as the John R. Wooden Award.
Memphis was seeded No. 1 in the South Region. Rose earned high praise for his increased focus on defense, hounding Texas Longhorn guard D. J. Augustin into a low-percentage game in the Elite Eight.In a match-up against UCLA in the Final Four, Rose finished with 25 points and 9 rebounds to lead the Tigers to an 85–67 win and a trip to the NCAA championship game against the Kansas Jayhawks.The win set an NCAA mark for most wins in a season.Against Kansas, Rose scored 17 points on 7–of–17 shooting, along with six rebounds and seven assists, but missed a critical free throw at the end of the second half as Memphis fell in overtime, 75–68.[Memphis concluded the season 38–2. Rose was named to the All-Final Four team after averaging 20.8 points, 6.5 rebounds and 6.0 assists per game.and losing in the state final championship game to Kansas jay hawks
On April 15, Rose announced he would forgo his final three seasons at Memphis and declared for the 2008 NBA draft.