The Spartans were led by 27th-year head coach Tom Izzo and played their home games at Breslin Center in East Lansing, Michigan as members of the Big Ten Conference.

7 seed in the West region, marking MSU's 24th straight trip to the NCAA tournament, the second longest active streak.

[12] Garrett Briningstool, an executive assistant to Izzo the past two years, was named director of basketball operations and chief of staff.

On April 12, junior forward Aaron Henry announced he would forgo his final two years of eligibility and enter the 2021 NBA draft.

[31][32] On February 3, 2021, Keon Coleman, a three-star wide receiver announced he would attend Michigan State to play football, but also said he would walk-on with the basketball team as a guard.

[35] On March 27, Northeastern point guard and 2021 Colonial Athletic Association Defensive Player of the Year Tyson Walker announced that he would transfer to Michigan State.

[37] On April 23, Purdue wide receiver Maliq Carr announced that he would transfer to Michigan State to play football and walk on to the men's basketball team.

[38] In July, it was announced that two more transfers had joined the team as preferred walk-ons: Jason Whitens from Western Michigan and Michael Peterson from Ferris State.

[48] Izzo announced on September 28 that the entire staff and all players in the MSU program (from the coaches on down to Breslin Center janitors) had been fully vaccinated against COVID-19.

The starting lineup consisted of Tyson Walker, Christie, Brown, Joey Hauser, and Marcus Bingham Jr.[57] The second game was against Grand Valley State on November 4.

[62] MSU returned to the road to play Butler at the historic Hinkle Fieldhouse for the Gavitt Tipoff Games on November 17.

Malik Hall, who started for Joey Hauser (minor calf injury), scored 15 while Gabe Brown added 10 as the Spartans pulled away for an 83–59 win.

[69] The first game of the tournament took place on November 24 as the Spartans took on former MSU graduate assistant and new Loyola coach, Drew Valentine.

On the ensuing play, Tyson Walker found Marcus Bingham wide open for an alley-oop dunk to give MSU the two-point lead with four seconds left.

20 in the Coaches poll, began its conference schedule with two early Big Ten games, first visiting Williams Arena to face undefeated Minnesota.

Aj Hoggard added eight assists as the Spartans missed Christie and Bingham defensively, allowing the Panthers to shoot 46% from the field including 52% from three.

Brown added two blocks and 14 points while Max Christie scored a career-high 21, shooting seven of nine from the field and making all four of his free throws.

Both Tyson Walker and Marcus Bingham did not play for the final 10-plus minutes as MSU went with a lineup of AJ Hoggard, Max Christie, Gabe Brown, Malik Hall, and Joey Hauser.

The Spartans struggled mightily in the game and trailed late as Northwestern, without their best player, Pete Nance Jr., led by two with less than 10 seconds remaining.

A traveling call after rebounding a missed Hall three-pointer that would have given the Spartans the lead, gave the ball to MSU with 0.9 seconds left.

AJ Hoggard scored 12 and added eight assists with only one turnover and hit eight of his 10 free throw attempts as MSU held on for the 86–74 win.

[91] Coleman became the first player to score a touchdown and a basket for AP top ten teams in both football and basketball since 1992 when Florida State's Charlie Ward quarterback/guard did so.

However, the Spartan offense began to struggle and the Terrapins climbed back in to the game, narrowing the lead to single digits several times.

In the prior game between the two teams, MSU had scored more than 30 fast break points, but Penn State limited the Spartans to only three in the rematch.

A turnover led to an offensive rebound and three-point play by PSU big man John Harrar with 35 seconds left put the Penn State lead at four.

The Spartan defense chose not to double team 7'4" Purdue center Zach Edey in order to limit the Boilermakers' three-point shooting.

Marble made two free throws to give MSU a two-point lead, but Trevion Williams tied the game again with 30 seconds remaining.

UM big man Hunter Dickinson torched MSU's interior defense and scored a career-high 33 points as the Wolverines took the early lead and never relinquished it.

The Spartans steadied their play, led by Malik Halls 17 points and Marcus Bingham's 11 rebounds to hold on for the 77–67 win.

However, Maryland guard Fatts Russell missed a three-pointer to take the lead with six seconds remaining and Christie made two free throws to put the game out of reach as the Spartans held on for the 76–72 win.