[16] Several players did sign free agent contracts following the draft: On January 27, 2021, safeties coach Mike Tressel, who had been on staff with MSU for 14 years, left the school to take the defensive coordinator position with Cincinnati.

[18] On January 28, the school announced that Travares Tillman, who had spent the previous year as a senior defensive assistant, had been promoted to cornerbacks coach.

[28] Running back Kenneth Walker III was named the winner Walter Camp Award as the college football player of the year as decided by a group of coaches and sports information directors.

The teams exchanged punts again, but the Wildcats got on the board when NU quarterback Hunter Johnson hit Trey Pugh for a one-yard touchdown pass with less than a minute left to play in the half.

MSU again started well, scoring on the first play from scrimmage for the second consecutive game as Payton Thorne threw a 75-yard touchdown pass to Jayden Reed on a flea flicker.

A 35-yard pass completion to Mosley moved MSU into Nebraska territory, but the drive sputtered inside the 10 and the Spartans settled for a field goal to return their lead to 10.

On third down, MSU defensive back Chester Kimbrough jumped a Martinez pass to intercept the ball and return it most of the waydown the field, but was unable to score as he was tackled at the Nebraska two-yard line.

The Spartan defense again forced a Hilltopper punt on the next possession and MSU moved quickly down the field as Walker scored on five-yard run to push the lead to 14–0.

WKU's next drive was helped by a targeting call against Halladay and the Hilltoppers scored on a one-yard pass to bring the game within two touchdowns with under nine minutes remaining.

The Spartans moved the ball into Scarlet Knight territory on the first drive of the game, but Kenneth Walker III lost three yards on fourth down at the Rutgers 22.

Rutgers took advantage of the poor play and moved into MSU territory, converting a third-and-18 early in the drive and scored on shovel pass from four yards out to take a 7–0 lead.

Indiana moved to MSU's two-yard line, but Angelo Gross sacked IU quarterback Jack Tuttle on third down to force a field goal attempt.

MSU linebacker Cal Haladay intercepted Tuttle's third-down pass and returned it 30 yards for the first touchdown of the game, giving the Spartans a 7–3 lead.

Following punts by both teams on their next possessions, MSU cornerback Chester Kimbrough sacked Tuttle and forced a fumble which he also recovered at the IU 23-yard line.

Thorne scrambled 22 yards for a first down to move the ball to midfield, but three plays later, his pass was tipped at the line of scrimmage and intercepted by Michigan.

MSU moved into Wolverine territory on the ensuing possession and Kenneth Walker III scored on a 27-yard run on the first play of the second quarter to narrow the lead to 10–7.

However, on the ensuing punt, Michigan's punter fumbled the snap and attempted to run for the first down, but was stopped short give MSU the ball at their own 40.

Looking to put the game away, Wolverine quarterback J. J. McCarthy fumbled the ball on the first play of the possession and Jacub Panasiuk recovered at the Michigan 41.

Another three-and-out by MSU led to a seven-minute and 14 second drive that ended with Purdue ahead 31–21 following another field goal early in the fourth quarter.

As MSU took over to start the second quarter, they moved downfield on a 14-play drive that was capped by a two-yard touchdown pass from Thorne to Heyward to push the lead back to 13.

Maryland was able to get close for a fourth and four play at the Spartan 24, but corner Ronald Williams Jr. broke up the fourth-down pass turning the ball over on downs.

OSU ran the ball only twice on the initial drive, moving quickly down the field and scoring on a 23-yard touchdown pass to take an early 7–0 lead.

The loss ended the Spartans chances at the Big Ten Championship and College Football Playoff as they dropped to 9–2 on the season and 6–2 in conference play.

After forcing Penn State into a three-and-out, the Spartans again quickly moved downfield and scoring on a nine-yard pass from Payton Thorne to Tre Mosley to take a 14–0 lead with just over six minutes remaining in the first quarter.

Thorne was then hit on a third-down scramble that appeared to be a targeting penalty that would have extended the drive, but no call was made and the Spartans were forced to punt from the back of their end zone.

Trailing for the first time in the game, the Spartans moved methodically down field on a 15-play, 75-yard drive capped by a Thorne one-yard quarterback sneak for the touchdown.

With weather conditions still making field goal attempts difficult, PSU elected to go for it on fourth-and-one, but were stuffed on the run play, turning the ball over to MSU with 12:43 left in the game.

[64] Walker and Heisman Trophy finalist Kenny Pickett, quarterback for Pitt, announced that they would not play in the game in order to prepare for the NFL draft.

The Panthers answered on the next possession, moving down the field on a 12-play, 75-yard drive capped off by Pickett's backup, Nick Patti, scoring on a 16-yard run to tie the game at seven.

On the next play, Cal Haladay repeated his Indiana heroics, intercepting Beville at the Spartan 22 and returning the ball 78 yards for a touchdown to give MSU an insurmountable 31–21 lead with 22 seconds left.