Trevor Knight completed just 10-of-20 passes with two interceptions and lost a fumble but threw a touchdown pass en route to 119 aerial yards for the Sooners (2-0, 1-0 Big 12).
Oklahoma's Damien Williams picked up 95 rushing yards on 21 carries.
The Mountaineers (1-1, 0-1) were led by Paul Millard, who went 21-of-40 passing for 218 yards and an interception.
Dreamius Smith picked up 77 rushing yards with a touchdown for West Virginia.
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