The friendly clash will take place on February 15 at Inter Miami's DRV PNK Stadium in Fort Lauderdale.
It will be the first time Messi goes head-to-head with the club he represented at youth level and who he supported as a boy.
Messi played for Newell's until the age of 13 before venturing to Europe to sign for Barcelona and join their famed La Masia academy.
Inter Miami boss Gerardo Martino will also face a familiar opponent after his own spell with the Argentine outfit as a player and manager.
Martino is the all-time record appearance holder for Newell's after representing the club on three separate occasions during the 1980s and 90s, winning four titles and another in 2013 as head coach.
Read more on Lionel Messi
'St Meeks' gets Messi lookalike to give Carragher Christmas present in wild prank
Lionel Messi record: Icon one of football's all-time top goalscorers as success continues
"I am delighted to welcome my beloved Newell's to our home here in Miami," said Martino.
"It will be a special match due to everything Newell's Old Boys means to me. It will also be a good opportunity to prepare for what will surely be an exciting season."
Inter Miami Chief Soccer officer and Sporting Director Chris Henderson was delighted the match could be arranged in front of what is expected to be a capacity crowd in south Florida.
Henderson said: "We're very pleased to be able to play this exciting pre-season match at home in front of our fans at DRV PNK Stadium.
Most read in Football
Ian Wright reveals real reason he is leaving Match of the Day
Former Tottenham boss favourite for Nottingham Forest job with Cooper on the brink
Van Dijk replies to Keane's arrogance claim after criticising Manchester United's tactics
Fulham to beat Man United, Liverpool and Arsenal to highly rated Brazilian in £20m+ deal
"This match against Newell's is a great addition to a set of matches that will put us in the best position possible to compete in 2024. We're excited for what is ahead."
Inter Miami's pre-season schedule boast six friendlies ahead of the new campaign including a blockbuster clash against Saudi Pro League side Al Nassr.
Lionel Messi beaten to MLS MVP as FC Cincinnati midfielder Luciano Acosta claims landslide victory
The game will see see Messi go up against long-time rival Cristiano Ronaldo for what could be the final time.
The pair have tussled for individual and team honours for the past 15 years and the friendly clash in February will provide Messi and Ronaldo with the opportunity to claim final bragging rights, or perhaps even show some unity as football's two modern greats to head-to-head.