But after an early stretch when Atletico neutralized host Barcelona's ball possession, Messi broke through with a perfectly stroked free kick that he set up by earning a foul from Thomas Partey.
The 24-year-old made little impact on an otherwise strong Barca performance and he was jeered by a small number of fans, with one such incident apparently prompting an angry reaction from head coach Ernesto Valverde.
That frustration summed up Atletico's day as their hopes of a second LaLiga title under Simeone suffered a significant blow, with 11 matches of the league season now remaining.
To paraphrase Gary Lineker: Football is a simple game.
Bernardo Silva scored the only goal of the match 35 seconds into the second half at the Etihad Stadium when he prodded home at the back post from mid-fielder David Silva's low cross.
Atletico striker Antoine Griezmann, meanwhile, who came in with seven goals in two games, was largely anonymous. Messi has single-handedly won Barcelona tough games in the past, and he was at hand on Sunday as well.
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"It seems pretty unlikely that Barcelona will lose three games, but we'll go on competing", Simeone said.
"If we take Messi and put him in an Atletico shirt, we win this match 1-0".
"Iniesta is a unique player, a little like Messi, so it's hard to find a player who can replace him", Valverde said when asked how he will substitute the club captain in the coming weeks. I was thought to always think in the next match, so we don't stray from our objective: keep improving.
Messi has been the standout player for the Catalans as he so often wins them games on his own.
Irrespective of their success on that front, it is inevitable there will continue to be speculation over the future of Simeone, who has been in charge since 2011 and previously stated he will leave the club if he feels he can no longer take them forward. "I think now there are two or three teams in the world better than Argentina - first Brazil, then Germany and Spain, and then us".