After near misses and emotional words on both sides, Mascherano is now Messi's manager after he replaced Gerardo Martino at Inter Miami this week.
Following Miami's disastrous exit in the first round of the MLS playoffs, Martino announced his own departure citing "strictly personal reasons" for his exit.
Whether it was his or the club's decision, there was no surprise at the end of Martino's tenure as Miami aim to maximize the limited time they have left with Messi.
Embarking on a new era, Miami have now hired one of Messi's closest former teammates and friends, Mascherano, who most recently oversaw Argentina's U23 team at the Paris 2024 Games.
Mascherano will have already fulfilled the number one requirement in managing Inter Miami, that being a close bond with Messi. And this renewed partnership has been a long time in the making.
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The two Argentininan legends have seen their careers tied to each other for much of the past two decades, starting with joint success at the 2008 Olympics in Beijing.
Country connection turned to club when Mascherano joined Messi at Barcelina in 2010 and from there, the duo flourished alongside each other.
For much of the next ten years, Mascherano and Messi were focal members of one of the most impressive clubs sides in recent history, winning five La Liga titles, five Copa del Reys, and two Champions Leagues together.
On top of that, the two legends sit first and second in the table of most caps for Argentina, Mascherano losing the lead to Messi who is now closing in on 200 senior appearances.
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But their physical time together and the titles won alongside each other is just the tip of the iceberg for a genuine friendship that has transcended much of their two careers.
Not always known for laying his emotions bare in public, Messi took the opportunity to mention Mascherano in a heartfelt message after passing the former Liverpool midfielder for most Argenmtina caps in 2021.
"I am proud to have been able to wear the blue and white as many times as my friend Masche whom I love very much, and who I have always respected and admired."
Meanwhile, Mascherano not only recognises the player Messi has been throughout this era, but even believes his greatness could have translated to other areas of the pitch.
"If Messi were a defender, he would perhaps be one of the best defenders in the world," he said.
"Sometimes, at Barca we played 1v1 and it was impossible to get past him. We had no chance against him!
"Sometimes, attackers know how to defend. Leo defends very well. He was very fast and when you tried to dribble past him it was impossible."
The relationship that has led to so much success for each of these two Barcelona and Argentina legends nearly reignited this summer, Mascherano making his best effort to get Messi on his side.
Despite Messi playing for Argentina in the Copa America, Mascherano who was in charge of their country's Olympic squad, did everything in his power to make Messi one of the three overage players in his group.
"I spoke with Leo and we agreed to keep talking," Mascherano said in March. "He has just started the season with Inter Miami and we still have some time until the Olympic Games. And we have to consider he also has the Copa América ahead this summer. It is not an easy situation.
"We have to see if he really has the energy to be there [in Paris]. It is not our intention to bother him or pressure him. We made him an invitation in advance and we gave him all the facts he needs to think about it and to talk with his club.
"It is not easy for him, either, to manage it with Inter Miami and the MLS and to be absent for a while. He will decide at the right time"
In the end, Messi at his advanced age chose not to play a second tournament of the summer and Mascherano's side were eliminated by hosts France in the quarter-final stage.
Still though, Mascherano has made no secret of his desire to manage Messi and work with his long-time friend once again. He even placed the decision of his own national team fate all the way back in 2016 on the outcome of Messi's choices.
Following a third successive defeat in an international final - this time to Chile in the Copa America - Messi announced his retirement from La Seleccion.
"The fact that a teammate and a friend, who is also the [Argentina] captain, said that he didn't want to come back anymore, made you think," Mascherano said.
"We all asked ourselves what we would do if Leo didn't return. Because behind that decision there was a reason."
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Messi ended up returning and Mascherano followed him. Now, for the third time in their careers - after Barcelona and Argentina - Mascherano is following his former club and country captain.
Whether Mascherano ends up as the answer to Inter Miami's MLS Cup quest, it is clear that his close relationship with Messi will remain at the centre of everything they aim to build in south Florida.