Southern Cal missed a slew of shots in the early going and No. 21 Colorado never gave the Trojans a chance to recover.
Josh Scott scored 20 points, Askia Booker had 13, and Colorado rebounded from its first home defeat to rout Southern Cal 83-62 on Saturday.
"We were getting every shot we wanted the first five minutes, we weren't making them, and we weren't getting stops on defenses which allowed them to push the lead up," said Southern Cal's Byron Wesley, who had nine points on 3-of-14 shooting from the field. "The first five minutes were the biggest part of the game, they were able to push the lead up to about 20 and we weren't able to bounce back."
Xavier Johnson and Jaron Hopkins had 10 points each for Colorado (15-4, 4-2 Pac-12), which sent Southern Cal (9-9, 0-5) to its season-high fifth consecutive loss. It is the worst start in conference play for the Trojans since opening the 2012 season with an eight-game skid.
The Trojans never led in the game and found themselves trailing 20-2 in the early going.
"We had a great energy to start the game and we missed five point-blank shots in the lane in the first three, four minutes of the game," first-year Southern Cal coach Andy Enfield said. "Then we turned the ball over when we had a layup. We basically missed 12 points to start the game. That enabled them to jump out on us and Colorado is an excellent team."
Omar Oraby and J.T Terrell both had 16 points to lead the Trojans, who trail the all-time series with Colorado 5-3, including an 0-4 mark in Boulder.
Colorado was coming off Thursday's 69-56 loss to No. 25 UCLA. It was the Buffaloes' first game without star guard Spencer Dinwiddie, who was leading the team in scoring, assists and steals when he tore his left ACL during a loss at Washington last Sunday. Colorado also lost Tre'Shaun Fletcher, a key reserve, for 6 to 8 weeks when he went down with a knee injury in the same game as Dinwiddie.
Younger players thrust into more prominent roles because of the injuries to Dinwiddie and Fletcher had difficulty producing in the UCLA loss. But it was a different story against the Trojans, with 11 of 12 Colorado players scoring.
"When the whole team gets in and everybody gets a piece of the victory, it's great," Booker said. "We can only feed off of this."
Trailing by 17 at halftime, Southern Cal started the second half by scoring four points, pulling within 40-27.
Colorado responded with a 9-0 run that included a highlight reel breakaway dunk by Hopkins, who moved into the starting lineup in place of Dinwiddie.
Byron Wesley hit a jumper for the Trojans to get them back within 49-29 with 15:14 left but the Buffaloes got a 3-pointer from Johnson to start another flurry, punctuated by Booker's 3-pointer that extended Colorado's lead to 59-32 with 12:41 left.
Soon after, the Buffaloes began emptying their bench and cruised to the runaway win.
Colorado raced to a 20-2 lead to start the game, spurred by a rugged defense that produced seven of the team's season-high 10 blocked shots in the first half.
Oraby briefly stalled Colorado's momentum by converting a three-point play and the Trojans managed to cut the Buffaloes' lead to 31-21 on a driving layup by Strahinj Gavrilovic. But Colorado closed the last 2:33 of the first half on 9-2 burst, including consecutive baskets by Scott and a 3-pointer by Booker that just beat the buzzer to take a 40-23 lead.