The Indianapolis Colts selected Nelson in the first round (sixth overall) of the 2018 NFL Draft. On May 11, 2018, the Colts signed Nelson to a fully guaranteed four-year, $23.88 million contract, including a signing bonus of $15.45 million. On November 1, 2018, Nelson was named the NFL Offensive Rookie of the Month for October, after he was part of an offensive line that hadn't allowed a sack in 156 straight dropbacks and had 200 rushing yards in back-to-back games for first time in 33 years. Nelson becoming the first guard to ever win the award, and he and Darius Leonard (who won Defensive Player of the Month in September) became the first teammates to win awards in the same season. He was named to the Pro Bowl as a rookie and was named first-team All-Pro.