Coach Alejandro Sabella has called-up the 23-year-old, who has notched three Premier League goals this term, for next month's friendly away to Saudi Arabia.
Di Santo, who has played for his country at under-20 level, Manchester City's Pablo Zabaleta and Sergio Aguero and recalled Newcastle United defender Fabricio Coloccini have been included in a 23-man squad named for the 14th November match in Riyadh.
"This is unbelievable. For any player in the world playing with (Lionel) Messi is the best," Di Santo said. "I will have a smile in my face for several days. This is something I have always dreamt, and now it's true."
Argentina squad in full:
Goalkeepers: Sergio Romero (Sampdoria), Mariano Andujar (Catania), Cristian Alvarez (Espanyol).
Defenders: Hugo Campagnaro, Federico Fernandez (both Napoli), Fabricio Coloccini (Newcastle United), Pablo Zabaleta (Manchester City), Ezequiel Garay (Benfica), Marcos Rojo (Sporting Lisbon), Luciano Monzon (Olympique Lyon).
Midfielders: Javier Mascherano (Barcelona), Fernando Gago, Alberto Costa (both Valencia), Enzo Perez, Eduardo Salvio (both Benfica), Angel Di Maria (Real Madrid), Fabian Rinaudo (Sporting Lisbon), Augusto Fernandez (Celta Vigo), Ricky Alvarez (Inter Milan).
Forwards: Sergio Aguero (Manchester City), Lionel Messi (Barcelona), Gonzalo Higuain (Real Madrid), Franco Di Santo (Wigan Athletic).