The duo dominated European football together in their Barcelona days with five LaLiga titles and two Champions League trophies.
They also combined for Argentina, which was a less fruitful relationship but did lead to Olympic gold in 2008.
It is a bold move from co-owner David Beckham after Gerardo Martino led Miami to a record-breaking MLS haul only to fall in the play-offs.
And Manchester United legend turned analyst Gary Neville thinks it was a master stroke from his former teammate to bring in 40-year-old Mascherano.
"Mascherano, having worked with the youth teams with Argentina, I think the way in which the MLS is, obviously, you've got these fantastic, wonderful stars in the team," he said on the latest episode of his It's Called Soccer podcast.
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"Then you have quite a group of players, sometimes that may be a little bit younger, that aren't as well-paid, it's almost like having two separate changing rooms.
"The money that the big stars are on is huge. So Mascherano, having worked with youth team players will maybe have that ability to be able to flip between dealing with the senior players, because he's played with the likes of (Jordi) Alba, and Messi, and (Sergio) Busquets.
"Then you think about the players that are the rest of the dressing room. How does he connect with them? How does he get the best out of them? How does he coach them?
"Working with younger players, I think he's obviously got that dynamic of being able to work with players and get them sort of together.
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"He could be a great fit and he knows Leo Messi and Leo Messi will obviously want to play for him, which is a big incentive."
Messi's seal of approval is a big deal.
And Neville thinks the superstar will have had a major say in the appointment.
"It's been accepted even at Barcelona in the last few years that he has an influence over who the coach is going to be," he added.
"I think even with Argentina as well.
"It's critical that he gets on with, and there are very few players who have that level of influence, but it's plainly obvious that he does."
Miami won the Supporters Shield this year after dominating in the regular season.
An MLS-record 74 points saw Messi & Co enter the postseason as overwhelming favorites.
Watch Lionel Messi accidentally hit a child in the face with a free-kick during an MLS game
But Atlanta United sprung a major upset to end Messi's MLS Cup dream.
The 37-year-old will know time is running out to be crowned MLS champ and Mascherano will need instant results or the heat will start to rise quickly.