The Argentine will face off against the Red Devils in the quarter-final of the Champions League, but how has he fared against them in the past?
Barcelona face Manchester United in their massive Champions League quarter-final match-up on Wednesday, and the two sides have plenty of history in the European competition.
The Red Devils' historic 1999 final comeback victory over Bayern, at Barca's Camp Nou home, has been lodged in football folklore, with former player and current manager Ole Gunnar Solskjaer's stoppage-time heroics securing the win.
While Barcelona were defeated in the 2007-08 semi-final by United, the Catalans have got the better of the Premier League side in recent seasons, defeating them in the final of the tournament in 2009 and 2011.
What is Lionel Messi's record vs Man Utd?
Messi has played against Manchester United four times in the Champions League, winning two, losing one and drawing one. He has scored two goals in the four appearances, though has registered no assists.
The first time he came up against the Red Devils was in the 2007-08 edition of the Champions League when Barcelona failed to win either leg of the semi-final. The first leg ended 0-0 at Camp Nou on that occasion, with the return meeting at Old Trafford resulting in a 1-0 win for the Red Devils, courtesy of a Paul Scholes strike.
Messi thus failed to score, with the result sending United through to face Chelsea in the final, which they won in Moscow courtesy of a penalty shoot-out.
His next two instances facing off against then-manager Sir Alex Ferguson's side have been more successful. Since the 2008 semi-finals, he has faced United in the final of the Champions League twice, scoring a goal in either final and ultimately leading Barcelona to European glory.
Messi scored the second in the 2-0 final win against the Premier League side in the 2009 final and he netted once again two years later in the 2011 version held at Wembley Stadium - a match that ended with a 3-1 victory for the Spanish giants.
He also scored the crucial second goal of the game which cancelled out Wayne Rooney's equaliser to make it 2-1 to Barcelona just after half-time. Pedro had opened the scoring, and David Villa then sealed the victory with the third goal late on in the second half.