After the arrival of José Mourinho as Manchester United manager in 2016, Varela came on as a substitute in Mourinho's first match in charge of the team (a 2–0 win away to Wigan Athletic in a friendly). However, he was not included in Mourinho's squad for the club's summer tour of China, and on 23 July 2016, Varela joined German club Eintracht Frankfurt on a season-long loan deal.
On 5 March 2016, following his emergence into the Manchester United first-team, Varela received his first call-up to the Uruguay senior squad, for the World Cup qualifiers against Brazil and Peru later that same month.