Second-half goals from Ever Banega and Manuel Lanzini secured the result for the home side as they laboured to a win.
The five-time Ballon d'Or winner was unable to take part for Jorge Sampaoli's side due to an 'overload' injury discovered during the week leading up to the friendly in Manchester.
Argentina, without their star man through injury, controlled the early goings but were unable to find a way past Gianluigi Buffon for the most part, ultimately labouring with their final ball.
Without Messi, there were little amounts of attacking magic.
Despite that, the Argentine's called upon a defensive midfielder to give them the lead.
Banega, on as a second-half substitute, linked up with Giovani Lo Celso on the edge of the Italy box before striking an effort low and hard past Buffon - leaving the goalkeeper rooted to the spot as the ball trickled home.
Lanzini added the second five minutes before full-time with a strike from just inside the 18-yard-box that was powerfully lifted over Buffon and into the back of the net.
Hosts edge early goings
The first period was edged by Argentina, hosts on the night at the Etihad, but neither side was able to break the deadlock.
Angel Di Maria had the lion share of the Argentine sides best efforts - forcing a number of saves from Buffon.
Di Maria, whose first few touches were booed, had Argentina’s first effort on goal when he struck low from the left-hand side of Buffon’s box and forced a save out of the veteran shot-stopper.
Current Manchester City man Nicolas Otamendi powered an early header goalwards but like even Argentina chance in the first-half, saw his chance denied by Buffon.
However, the best chance fell to Leandro Paredes five minutes before half-time as the midfielder unleashed an effort from distance. His chance skidded just wide of Buffon’s left-hand post but the veteran keeper seemingly had it covered.
The Italians answered with their own early effort but Marco Parolo could not direct his header goalwards, instead, looping over the bar of Willy Caballero.
Insigne sitter denies Italy a lead
Quickly after the restart, Italy had a golden chance to take the lead but for an absolute sitter from Lorenzo Insigne.
Ciro Immobile capitalized on a stray ball between the Argentine defenders and laid a ball off to his strike partner. However, when he found himself one on one with Caballero, Insigne could not direct his effort on goal - missing spectacularly.
The Italians had another golden chance before the hour mark but Caballero was able to deny Immobile as the striker drifted in, unmarked, from his far post.
The save resulted in a corner which resulted in an effort from Alessandro Florenzi that failed to trouble the keeper.
Second period quality seals proceedings
In a game with numerous attacking stars on display, a goal from a midfielder - a defensive midfielder at that - wouldn't have been the first choice of goalscorer from the viewing fans.
Banega's strike, that left Buffon rooted to the spot as the ball trickled past him, showcased what Argentina had been missing due to Messi's absence.
His link-up play with young Lo Celso was superb and looked remarkably similar to the attacking style that Messi brings to the fold.
Lanzini's goal, minutes before time, wrapped up the win for Sampaoli's side as their second-half quality ultimately showed.
However, they wouldn't have been in a position to pick up a victory if it weren't for a number of speculative saves from Willy Caballero, showcasing their ability to wade off attacks.
Caballero may not be the number one for Sampaoli when the World Cup rolls around in the summer, but a showing like the one put in at his former stomping ground won't steer him far wrong.