Barkley was 16-of-25 for 290 yards with two interceptions.
Stanley Havili caught five passes for 107 yards and one touchdown while adding another score on the ground for the Trojans (4-0, 1-0 Pac-10), who are not only banned from postseason play, but also from challenging for a conference title due to NCAA penalties.
Jeff Tuel completed 24-of-37 passes for 222 yards with one touchdown and three interceptions for the Cougars (1-3, 0-1), who have lost 12 in a row to FBS opponents.
Jared Karstetter had 87 yards and two scores on eight receptions in defeat.
Washington State got the ball to begin the game and used a little trickery in taking an early 7-0 lead. On first down from the USC 29, Tuel dished to wide receiver Jeffrey Solomon and he found Karstetter in the end zone.
The Trojans answered on their first play from scrimmage, as Havili rumbled 59 yards for a touchdown. Tuel was picked off on the second play of the next series and Nickell Robey's 25-yard return put USC up 14-7. The game was not even four minutes old at that point.
USC's quick-strike offense struck again following a WSU punt. Starting from his own 24-yard line, Barkley hit Havili for a 58-yard gain. Allen Bradford then ran for seven yards before Barkley extended the lead to 21-7 with an 11- yard TD pass to Robert Woods with 6:52 remaining in the opening frame.
The second quarter featured a litany of mistakes.
WSU converted a Barkley interception into a six-yard TD pass from Tuel to Karstetter. However, the extra point was blocked.
Bradford fumbled on USC's next possession, but Tuel was immediately picked off again by Robey. Barkley took the Trojans 62 yards on 13 plays, with Marc Tyler's two-yard TD run capping the time-consuming drive.
Tuel threw another interception on the next series and the Trojans had a chance to add to their lead, but Joe Houston missed a 39-yard field goal as the half expired.
Following the break, Barkley engineered a four-play, 93-yard drive to start the third quarter. The sophomore signal-caller hit Brice Butler for a seven- yard score, and a two-point conversion gave USC a 36-13 lead.
The Trojans led by 30 points after Ronald Johnson hauled in a seven-yard TD pass from Barkley later in the third.
Mitch Mustain completed a 22-yard TD pass to Havili in the fourth quarter.
WSU recorded the final points of the game on Nico Grasu's 44-yard field goal.
Bradford rushed for 84 yards and Havili had 80 yards on four carries...Lane Kiffin became the first USC head coach since Jess Hill in 1951 to begin his Trojan career at 4-0...The Cougars have dropped eight in a row to USC...Washington State was winless against conference foes last season.