Messi is absent for the current round of international fixtures as he continues to recover from an ankle injury that he sustained in the 2024 Copa America.
With Messi unavailable, Dybala was given the privilege of wearing the iconic number 10 jersey for Thursday's home meeting with Chile.
Dybala, who was a late call-up to the squad, came off the bench in the 79th minute when Argentina were leading by a narrow 1-0 scoreline following Alexis Mac Allister's opener.
Atletico Madrid's Julian Alvarez doubled the advantage before Dybala fired home a third in stoppage time to wrap up a comfortable victory.
Dybala comments on donning Messi's shirt number
Speaking after the game, Dybala admitted that he was unsure whether he should accept the honour of wearing Messi's number 10 shirt.
Dybala told TyC Sports: "Being able to come back, being here with my teammates, with our spectacular people who support me a lot and the truth is that well, it's special.
"I know it's not my shirt, we all know it's Leo's shirt but well, I tried to represent it in the best way, to give my best and I think I was able to do it.
"It was a decision made by the coaching staff, some of the boys said that it had to be me. I didn't know whether to accept it or not because, well, it is a responsibility."
Scaloni praises Dybala
Head coach Lionel Scaloni insisted that Dybala deserved to have the privilege of donning the number that was also worn by Argentina great Diego Maradona.
"I think he is a player who deserves the 10," Scaloni said in his post-match press conference. "We simply put the list together and since we had to use the number 10 we made this decision.
"We tend to put too much weight on that number when in reality it should be an honour to wear it. Paulo has enough experience to wear such a decorated number. He's a player who makes the difference when he's fit and can give us a lot."
Dybala will now hope to make an impact in Argentina's next World Cup qualifier against Colombia in Barranquilla on Tuesday.
Argentina are currently sitting at the top of the standings after winning six and losing one of their seven qualifiers.