In January 2010, Smalling signed a pre-contract agreement with Manchester United and joined them officially on 1 July.

He made his competitive debut in the 2010 FA Community Shield victory over Chelsea which earned him his first career medal.

Since his debut, he has gone on to make more than 100 appearances for the club.

On 11 February 2015, Smalling scored the first brace of his career, and became the first player in the history of the Premier League to score 2 first half goals as a substitute, after appearing as a fifth-minute substitute in a 3–1 victory against Burnley.

On 12 April 2015, he scored his fourth goal of the season in a 4–2 win over Manchester City.

On 21 April 2015, Smalling signed a new contract with Manchester United, keeping him at the club until June 2019.

Having been praised by manager Louis van Gaal for his command of the defensive unit, Smalling captained United for the first time on 17 May 2015 during a 1–1 draw against Arsenal.