Franco Di Santo featured for both the u-20 team and the senior team during his time with the Argentine national team. The striker began his national team career in the u-20 set-up and he went on to score five times in 25 appearances over a three-year period. Franco Di Santo played for the u-20 team for the first time in 2006 and his last appearance for the team was in 2009.

Di Santo registered his first goal for the u-20 team against France. He was part of the Argentina u-20 squad to the 2007 edition of the South American Youth Championship in Paraguay. Franco Di Santo was unable to inspire his team to win the tournament after finishing second to Brazil who won via a two-point advantage. The striker was also given an invitation for the 2009 edition of the South American Youth Championship in Venezuela, but it was blocked by Premier League outfit Chelsea mainly due to the injury crisis at the club. Franco Di Santo had an average of one goal in five games over the course of his time with the u-20 team.

Franco Di Santo had to wait for three years before he was called up to the senior team. He was given an invitation to the senior team by manager Alejandro Sabella on October 31, 2012 ahead of the international friendly clash with Asian team Saudi Arabia in a few weeks. The Saudi Arabia game was held on November 14, 2012.
Di Santo earned a recall to the senior team in May 2014 ahead of preparations for the World Cup tournament in Brazil. He was a surprise inclusion in the 30-man provisional list for the tournament. However, he was cut from a second 26-man list later in May 2014. Di Santo was one of fout players dropped from the list.