Darnold threw for 329 yards as he improved to 18-3 as a starter. Tailback Ronald Jones II had 142 yards to surpass Mike Garrett for sixth place on the Trojans' all-time rushing list.
Southern Cal (9-2, 7-1 Pac-12, No. 11 CFP) led 27-0 in the third quarter, but needed to weather a late Colorado comeback. The Trojans blocked two field goals to move to 12-0 against the Buffaloes (5-6, 2-6).
Juwann Winfree had a big day for Colorado by hauling in TD passes of 79 and 57 yards. Steven Montez threw for 376 yards.
A pivotal play in the game was when Colorado tried to get something going with about a minute left before halftime and down 14-0. Montez forced a pass to the outside that Harris stepped in front of, tip-toed along the out-of-bounds line and headed into the end zone.
Harris had another interception in the fourth quarter that nearly went for a score. As he was being tackled, Harris pitched the ball to Marvel Tell III, who took it about 27 yards for a TD. The replay booth took a look and ruled that Harris' knee was down before the pitch.