Rex Burkhead rushed for a career-high 170 14.
The previous five meetings between the schools were all played in Lincoln, Nebraska, with the Cornhuskers winning each game.
Taylor Martinez completed 12-of-21 passes for 157 yards and a score. He also carried the ball 12 times for 37 yards with a touchdown for Nebraska (4-0).
Brett Smith went 17-for-33 for 166 yards, two touchdowns and a pick for Wyoming (3-1).
Mazi Ogbonna and Robert Herron each caught touchdown passes for the Cowboys.
"There are a number of things that we can correct and we will become a better team because of this game," Wyoming head coach Dave Christensen said.
After trading punts on the first three possessions, Nebraska broke the scoreless tie. Wyoming was forced to punt from its own end zone and Austin McCoy managed just a 39-yard kick, placing the ball on the Wyoming 45-yard line. Burkhead took the handoff on first down and rushed towards the left side. He received a couple key blocks and broke down the field for a 45-yard score.
Each team's defense held until the Cornhuskers took over at their own 20-yard line with 9:18 remaining in the first half. On 3rd-and-6, Martinez hit Quincy Enunwa for a 30-yard gain and Burkhead rumbled for 22-yard gain on the next play. Four plays later, Martinez ran it in from the eight-yard line to put Nebraska up 14-0.
But Wyoming recorded its own 80-yard drive on its next possession to make it a seven-point game again. The eight-play drive was capped with a 48-yard catch- and-run by Ogbonna in which he caught the ball over the middle and broke two tackles on his way in for the score.
Nebraska then drove down the field, but Brett Maher just missed a 50-yard field goal to the right as time expired in the half to keep it a 14-7 game.
Tim Marlowe returned the opening kickoff of the second half to his own 44-yard line, and two personal foul penalties on the Wyoming defense helped the Cornhuskers drive down the field, resulting in a Burkhead TD run from 16 yards out.
"Rex has been playing like that all year, and it doesn't surprise me. I think Rex is a heck of a player," Nebraska head coach Bo Pelini said.
After the Cowboys failed to convert a fourth down on a fake field goal, the Cornhuskers took over at midfield. A 44-yard catch by Kyler Reed set up a 20- yard field goal by Maher, putting Nebraska ahead 24-7.
A fumble recovery gave Wyoming the ball at its own 47. Herron's 21-yard run and a defensive pass interference penalty moved the ball to the Nebraska 15- yard line, but the drive stalled there and Daniel Sullivan's 32-yard field goal missed wide right.
On the ensuing possession, Nebraska ran on 7-of-9 plays before Martinez found Kenny Bell in the end zone for an eight-yard score.
Wyoming answered with a 14-play drive, resulting in a 10-yard TD pass from Smith to Herron. Smith completed 7-of-11 passes for 67 yards on the drive.
But Nebraska's offense was able to run out the majority of the clock with an 11-play drive capped by a one-yard score by Braylon Heard. P.J. Smith's interception allowed the Cornhuskers to run out the remainder of the game.
This was Burkhead's second straight 100-yard performance...Nebraska out gained Wyoming on the ground 333-137...Wyoming took the edge in the air 168-157...The Cornhuskers converted 7-of-13 third downs, while the Cowboys converted on 7- of-17 tries...Wyoming went 1-for-2 on fourth downs.