The David Beckham-owned Florida team blasted into the post-season with 74 points - a record for the US league - but they were still dumped out at the first hurdle by Atlanta United.
Atlanta themselves only squeezed into the play-offs with a lowest-placed finish of ninth, but after downing CF Montreal, they did the same to Miami in a best-of-three tie to cause an almighty shock and reach the final eight of the competition.
The result left Messi and Beckham reeling, and Atlanta assistant Carl Robinson told talkSPORT how it came about.
When asked about how to stop the Argentine World Cup-winning captain, he explained: "The relationship that Messi has with Jordi Alba, Luis Suarez and [Sergio] Busquets is crazy.
"Alba can be running down the left and Messi can be stood inside the centre circle and instead of crossing it he reverses it back into Messi's feet.
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"You have to be aware of every moment those four players are on the ball because the link-ups that they have with each other is incredible.
"You had to be in control of the game when you didn't have the ball and that was a big focus that we went into the game with and fortunately I think it worked."
Atlanta are now looking to add to their one and only MLS Cup in 2018 and face Orlando City up next.
Yet the ramifications of their win over Miami will go on and on, with the Florida side boasting a squad of astonishing talent.
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Along with their Barca quartet, the team have Paraguay regular Diego Gomez and Fernando Redondo's son Federico, while there are plenty of rumours that Neymar could also be playing in pink next season.
In the dugout is former Argentina and Barcelona manager Gerardo Martino who even won the cup with Atalanta in 2018.
So Robinson knows just how big an achievement it was for his side, but feels it was fully deserved.
"You look at the level of players they have and they've built a dream team," he said of Miami.
"They finished the regular season with 74 points which is the best ever for an MLS team and we snuck into the play-offs in ninth.
"It's like the old FA Cup in the quarter-finals or semi-finals, it's 11 against 11, we had a three-game series against them, we lost the first game 2-1 at their place and beat them at home in front of 70,000 in Atlanta and then we went down to their place again and beat them 3-2.
"So over the course of a three legged series I think we deserved it because we managed to beat the best team in the league twice."