Missouri quarterback James Franklin committed four turnovers in the second half: three interceptions and a lost fumble at the Oklahoma State 4.
''I know that I didn't play the best,'' Franklin said. ''And it's frustrating. But being sad about it isn't going to do anything about it.''
Randle had 138 yards on 14 carries and scored on runs of 16, 59 and 12 yards. He also caught a 13-yard touchdown pass in the second quarter.
''He's a big play waiting to happen,'' Weeden said. ''The guy is explosive. Without looking at the tape, he's got to be our MVP.''
Weeden had three touchdown passes after the opening snap of the second quarter. Lewis' interception and fumble recovery helped the Cowboys (7-0, 4-0 Big 12) pull away and win their ninth in a row on the road despite injuries to both starting wide receivers.
They're 7-0 for just the third time in school history, also doing it in 2008 and 1945. A major reason: They've forced 22 turnovers the last five games.
''They gave us what we had been working on all week,'' defensive end Jamie Blatnick said. ''When we see what we've prepared for it works out for us.''
Justin Blackmon caught a touchdown pass in the first quarter but was held out the second half as a precaution after taking a blow to the head. Hubert Anyiam, the Cowboys' third-leading receiver, is out for the season with a broken bone in his left foot.
Isaiah Anderson had a career-best five receptions and Tracy Moore matched his career best with seven receptions.
''It's interesting how young men will play when they know they have to play,'' coach Mike Gundy said.
Henry Josey had 138 yards on 25 carries and T.J. Moe had six catches for 103 yards and a score for Missouri (3-4, 1-3), which has yet to win consecutive games and has dropped three straight in the series. All four of the Tigers' losses have come against teams ranked at the time, and they play at No. 18 Texas A&M next week.
''We adjusted at halftime and played a little better,'' defensive end Jacquies Smith said. ''But we didn't make enough plays.''
The Tigers had a strong second quarter, scoring on an 18-yard run by Kendial Lawrence and Moe's 34-yard catch from James Franklin to cut the deficit to seven, before being undone by mistakes.
Lewis intercepted a tipped pass at the Missouri 27 and three plays later Randle scored on a 16-yard run for a two-touchdown cushion midway through the third quarter.
Missouri appeared to regain momentum when E.J. Gaines intercepted Weeden in the end zone and returned it 54 yards, also ending Weeden's string of 194 consecutive passes without a pick. Franklin's lost fumble gave the Cowboys possession at the 12, and again they needed just three plays to respond with Randle's 59-yard jaunt making it 38-17. Brodrick Brown's interception and 21-yard return set up Randle's fourth TD in the final minute.
''We had opportunities,'' Pinkel said. ''Against a team like this, a really, really good team, we have to take advantage of every single opportunity.''
Weeden was 33 for 49 for 338 yards after a sizzling start and extended his streak of 30-yard completions to 15 games. The 28-year-old senior was 19 for 25 for 214 yards in the first quarter, with all six incompletions on drops.
''We may score 40 in the first half if we just catch the dang ball,'' Gundy said. ''We have to clean that up this week.''
Michael Harrison was wide open on a 27-yard catch and Blackmon caught an 8-yarder for his 28th receiving touchdown in 19 games. On the first play of the second quarter, Oklahoma State went up 21-3 on Weeden's 13-yard TD pass to Randle.
Trickery produced Missouri's best play of the quarter, with Franklin throwing a lateral pass to Moe and then getting it back for a 31-yard gain to the 13. But the Tigers stalled, settling for a short field goal by Grant Ressel.