The 2014 finalists play their second fixture of 2018 against a Spain side who drew to Germany on Friday evening, having beaten Italy 2-0 at the Etihad Stadium last time out.
Messi was named in the squad to travel to Manchester but played no part in the fixture, though is hopeful of a spot in the starting XI on Tuesday.
But if things had been different, could Messi have been lining up on the other side at Wanda Metropolitano? Goal investigates.
Could Messi have played for Spain?
With Italy out of the picture early on, it was a straight shootout between Messi's country of birth, Argentina, and country of residence who he qualified for due to a Catalan great grandfather who was born in Balaguer, Spain, for his services.
Following Messi's move to Barcelona, the club's director of football, Carles Rexach, pushed for the Royal Spanish Football Federation to secure the future of the player.
After three goals in those two games and 11 in his next 16 for the Under-20 team, Messi was promoted to the U23s and eventually the senior side.
“When I was a kid I expected to get a call from the AFA [Argentinian Football Association]," Messi said in his book, Messi, The Patriot. "I was asked informally if I wanted to play for Spain, but I always said that I wanted to play for my national team because I love Argentina and these are the only colours I want to wear.
“I was always an avid fan of the national team. I watched the games on television because I could never go to the grounds and watch them as a fan."
Former Barca team-mate Cesc Fabregas has since backed Messi's decision to pick Argentina over Spain, though believes La Roja have missed out as a result.
"It would have been phenomenal if Leo had played for Spain," The Chelsea midfielder said. "We would have won more titles, but he always felt very Argentine and I think it was the perfect decision to play for his country."
Could Messi have played for Italy?
Born Lionel Andres Messi Cuccittini, the future Barcelona star's parents both had Italian ancestry.
Messi would indeed have qualified for an Italian passport through his great grandfather, who moved from Recanati to Messi's place of birth, Rosario, in 1883.
There is nothing on record to suggest that the Italian Football Federation attempted to persuade a young Messi to commit to the Italian set-up, however, and with both Argentina and Spain pushing for his services, it was never on the cards for him to don the royal blue of Italy.
Other Italian Argentine footballers
Mauro Camoranesi, capped 55 times by Italy, was born in Tandil, Argentina.
Raimundo Orsi, winner of five Serie A titles between 1930-1935, was also eligable to represent both countries, and made appearances for both. Orsi played for Argentina between 1924-1928 before switching allegiances for six years, winning the World Cup for the Azzurri, and even returning for Argentina duty for a game in 1936.
Omar Sivori, Humberto Maschio and Antonio Angelillo, nicknamed the Angels with Dirty Faces, all played for both Argentina and Italy, as did Luis Monti, also formerly of Juventus.
Current Juve star Paulo Dybala is also eligible to play for both Italy and Argentina, as well as Poland, but chose to commit to the Albiceleste.
“I feel 100 per cent Argentinian, though I look foreign with these pale eyes,” Dybala previously told La Repubblica. "When I had to choose, I had no doubts. I didn’t make any calculations. I know that I’d have less competition for Italy or Poland, but I want to play for Argentina and I never asked questions or thought about switching sides.
“I wouldn’t be happy in a national team that didn’t feel like mine, to hear an anthem that isn’t my own, in colours that don’t belong to me. My friend Franco Vazquez has an Italian mother. I only have an Italian passport thanks to a great-grandmother who I know nothing about. He feels Italian, I don’t.”