Surprisingly, it was the 155th-ranked nation by FIFA in Puerto Rico who had the first shot on target, as Leandro Antonetti almost caught Emiliano Martínez out from distance.
The goalkeeper managed to stop his astonishing effort from flying over the line in what was an early scare for Argentina.
However, they regrouped and controlled the rest of the first half and not long after that, they took the lead.
Messi hit the crossbar with an initial strike as the ball ricocheted out to Nicolas Gonzalez. He then fired back towards goal and Alexis Mac Allister headed home.
Messi was involved again soon after as his delightful pass found Gonzalo Montiel, and he lashed in just his second international goal with a crisp volley.
Mac Allister got on the scoresheet again as Argentina made it three before half-time, rifling into the top corner after Jose Lopez, on his international debut, laid the ball off to him.
Martinez was called into further action when he parried away Wilfredo Rivera’s long-range effort, but Argentina were largely comfortable.
The World Champions continued to push for more goals in the second half, and Messi came close to scoring again as his header at the back post was well-saved by Sebastian Cutler de Jesus.
The fourth actually came from a Puerto Rico player in Steven Echevarria, who unfortunately diverted Gonzalez’s shot into his own net.
Messi was still desperate to score in his adopted homeland, but Cutler de Jesus palmed another of his shots away.
Substitute Lautaro Martinez got amongst the goals though, recording his sixth and seventh goal involvements in five appearances for club or country.
He first poked home Gonzalez’s cutback before Messi set him up to place into the bottom corner.
Argentina flexed their muscle in the end with 10 of their last 11 wins now being accompanied by a clean sheet, while Puerto Rico’s rotten record against CONMEBOL teams continues with no victories in seven head-to-heads.
Flashscore Man of the Match: Alexis Mac Allister (Argentina)