On 2 July 2016, Dortmund chief executive Hans-Joachim Watzke said that the sale of Mkhitaryan to England's Manchester United would be inevitable as the player would leave for free had he stayed one more year.

Four days later, Mkhitaryan joined them on a four-year contract for a transfer fee reported variously as between £27 million and £30 million, with the option to extend for a further year.

He became the first Armenian to join a Premier League club. He made his first Premier League start for Manchester United in the Manchester derby on 10 September 2016, but he was substituted at half-time.

On 8 December 2016, Mkhitaryan scored his first goal for the club, away against Zorya Luhansk, in Manchester United's last group match of the Europa League.

Three days later, in United's next game, Mkhitaryan scored his first Premier League goal (and his first goal at Old Trafford) in a 1–0 victory over Tottenham Hotspur; however, he left the game in the second half after suffering an ankle injury in a tackle by Danny Rose.

He returned from this injury two matches later, coming off the bench to score United's third goal against Sunderland, a scorpion kick which he described as being the best goal he had ever scored.