He played college football for the Notre Dame Fighting Irish, receiving unanimous All-American honors in 2017, and was selected by the Colts sixth overall in the 2018 NFL draft.

Considered among the NFL's best guards, Nelson has received Pro Bowl selections in all seven of his seasons and three first-team All-Pros.

[13] At the conclusion of the pre-draft process, Nelson was projected a top ten selection in the first round by NFL draft experts and scouts.

He was ranked as the top offensive linemen prospect in the draft by Sports Illustrated and NFL analysts Daniel Jeremiah and Mike Mayock.

[31] On April 28, 2021, the Colts exercised the fifth-year option on Nelson's contract,[32] which guarantees a salary of $13.754 million for the 2022 season.

[33] On August 3, it was revealed that Nelson needed surgery on his left foot, a similar injury that Carson Wentz had suffered a week prior.

[38] Nelson became just the second player in team history to earn Pro Bowl honors in his first four seasons, joining Alan Ameche (1955–58).

He also became the first offensive lineman in the NFL to do it in his first four seasons since Zack Martin (2014–17) and is the first Indianapolis player to be selected to four consecutive Pro Bowls since T. Y. Hilton (2014–17).