The ninth-seeded Wildcats (14-18) gave the Cornhuskers (30-0) all they could handle for a half from before Griffin started to take over.
Cory Montgomery scored 13 points and Dominique Kelley added 11 for Nebraska, which plays either Texas or Texas A&M in a Saturday semifinal.
Jalana Childs and Kari Kincaid led K-State with 10 points apiece.
The Huskers came into the Big 12 tournament believing they needed one win to secure a No. 1 seed in the NCAA tournament.
K-State caused some anxiety in the first half, trailing 27-26 at the break after holding the Huskers to 33 percent shooting and controlling the boards.
Griffin scored nine points during an 11-5 run that turned a 32-31 Nebraska lead into a 43-36 bulge. A 13-2 spurt all but finished off the Wildcats, and the lead grew to 21 points in the last three minutes.
Kansas State suited up just seven players. Kelsey Hill, Shalin Spani and Alina Voronenko sat out with injuries.
The Huskers' uptempo game took a toll on the Wildcats, who were playing for the second straight day after beating Texas Tech 59-51 on Thursday.
Griffin, who scored a career-high 36 points in the Huskers' 82-72 win over the Wildcats on Saturday, was the focal point as Nebraska broke things open in the second half.
K-State had chances to tie or take the lead early in the second half. But Brittany Chambers missed two free throws when the Wildcats were down by a point, and Griffin drew charges from Ashley Sweat and Childs.
In the teams' previous meeting, the Wildcats had a seven-point lead at halftime. Nebraska used a 22-7 run to start the second half to take control of that game.
The Huskers looked like anything but an unbeaten team early Friday. But K-State couldn't capitalize, committing 15 turnovers against the Huskers' full-court defense and missing 11 of its first 14 shots.
Griffin scrambled through the lane to put back her own miss for a 27-22 Nebraska lead 2:27 before the break. The Huskers didn't score again until the second half.
Sweat took advantage of a defensive breakdown to stroll in for an uncontested layup, and Mariah White went strong to the basket to make it a one-point game at the break.
The Huskers never found their touch from long range, missing 18 3-pointers in a row before Montgomery scored from long distance with 7:44 left in the game.