As a true freshman at Minnesota in 2016, Winfield Jr. played in 12 games and made nine starts. During the season, he had 52 tackles, one interception and one fumble recovered for a touchdown. He played in the first four games in 2017 before suffering an injury that caused him to miss the rest of the season. He finished the season with 20 tackles and a sack. Winfield Jr. again played in only four games in 2018, recording 17 tackles and an interception. He returned from the injuries in 2019 and was named a finalist for the Bronko Nagurski Trophy. After being named a first team all American and Big Ten Defensive Back of the Year during the 2019 season, Winfield announced that he would forgo his final 2 years of eligibility and declared for the 2020 NFL Draft.

Winfield made his regular season debut in Week 1 during a 34–23 loss to the New Orleans Saints, recording 6 total tackles and 1 pass deflection. In Week 2, during a 31–17 win against the Carolina Panthers, Winfield recorded 11 total tackles as well as his first career sack on Teddy Bridgewater which resulted in a fumble that was recovered by teammate Jason Pierre-Paul. In Week 3, during a 28–10 win against the Denver Broncos, Winfield recorded 6 total tackles, 1 pass deflection, and a sack. On October 1, 2020, Winfield was named the NFL Defensive Rookie of the Month for his performance in September (23 total tackles, 2 pass deflections, 2 sacks, and 1 forced fumble from Weeks 1–3). In Week 7, during a 45–20 win against the Las Vegas Raiders, Winfield recorded 2 total tackles, 1 pass deflection, and his first career interception off of a pass thrown by Derek Carr.