McCoy completed his first 11 passes and produced touchdowns on No. 3 Texas' first three drives, helping to put the Tigers away early in a 41-7 victory on Saturday night.
McCoy matched his season best with three touchdown passes, two of them to Jordan Shipley, while Texas' defense blocked a punt for a score in a nearly flawless first half that produced a 35-7 lead.
"Colt has had a very tough year," coach Mack Brown said. "He's been sick, he's been hurt, but he's tough. We've got the Colt of old back now and ready to make the stretch run."
McCoy's on-target performance helped Texas win its 11th in a row overall and he's 39-7 overall at Texas, tying Tennessee's Peyton Manning for second in career victories.
"It's amazing what not being sick will do for you," he said. "I felt great out there tonight. The weather was awesome."
The Longhorns (7-0, 4-0 Big 12) beat Missouri for the sixth straight time and Blaine Gabbert was held to 84 yards passing and a touchdown before getting pulled late in the third quarter.
"Just a lot of mistakes," Missouri coach Gary Pinkel said. "I don't care if it's the New England Patriots, I expect them to play better than that."
The Tigers (4-3, 0-3) have opened conference play with three straight losses for the first time since 2002 and by a combined score of 95-36 although the toughest stretch of the season by far is over with Missouri at Colorado (2-5) next week.
"It's a pivotal point of the season, obviously, it doesn't take a rocket scientist to figure that out," Pinkel said. "If we don't start playing better, you're never going to win a game."
The last one was essentially over by halftime, too, with Texas leading 35-3 last year in Austin en route to a 56-31 thrashing, and in those two games Missouri has been outgained 637-203.
This was Missouri's most lopsided loss in the series since 65-0 in 1932 and worst home loss since a 38-0 loss to Kansas State in the 2002 finale.
A homecoming crowd of 71,004, the largest since Faurot Field was reconfigured in 1995, was silenced early. Thousands were headed home by halftime and the stands less than half-full early in the fourth quarter.
McCoy was 26 for 31 for 269 yards with an interception. Shipley had seven catches for 108 yards, his fourth 100-yard game of the season, with scoring catches of 8 and 13 yards.
"Our defense has been playing lights-out, and we wanted to give them something to play for," McCoy said. "This is the biggest team sport there is, and when you can have 11 guys playing together every snap, you win like this."
Texas is 31-4 against the Big 12 North since 1998 and Brown is 6-0 against Missouri, the two-time defending division champions.
Gabbert was 8 for 16, including a touchdown, before getting pulled late in the third quarter. Gabbert had been hobbled by a sprained right ankle the previous two weeks, but his problems appeared to have more to do with Texas' stifling defense.
Pinkel said Gabbert was taken out as a precaution and would have kept playing if Missouri had made a game of it.
McCoy totaled one touchdown pass the previous two games and had been a bit of a question mark this week due to a bruised right thumb. Instead, Texas led 21-0 late in the first quarter.
McCoy opened 9 for 9 for 106 yards, also hitting John Chiles for a 34-yard score, and the Longhorns had a 170-1 advantage in total yards before Missouri got anything going.
The Longhorns scored a pair of touchdowns in the final two minutes of the half. McCoy hit Shipley for a 13-yard score and Curtis Brown blocked a punt in the end zone that was recovered by Malcolm Williams.
"The blocked punt, that's just ridiculous," Pinkel said. "There was nothing special on that."