Ahmadinejad will meet fellow US foe and firebrand Venezuelan President Hugo Chavez during a four-nation trip that coincides with rising international concern over Tehran's nuclear ambitions.
The Iranian leader will arrive in Caracas late Sunday, kicking off a five-day trip that will on Tuesday see him attend the inauguration of the recently re-elected Nicaraguan leader Daniel Ortega.
Stops in Cuba and Ecuador will round off the tour. All four Latin American countries have frosty ties with the United States and their leaders have in the past four years made numerous visits to Tehran to build up diplomatic and business links while relations with Washington have worsened.
Ahmadinejad's international affairs director, Mohammad Reza Forqani, said the visit to "what used to be called the backyard of America shows the dynamism of the Islamic Republic of Iran's diplomacy in the world arena."
The trip also "invalidates the claims of the enemies," Forqani was quoted as saying by Iranian state media on Tuesday, in a clear jab at Washington.
Officials in Ecuador meanwhile confirmed Ahmadinejad would visit the South American nation on Thursday, in the Iranian leader's second visit since attending President Rafael Correa's inauguration in 2007.
Ahmadinejad will talk with Latin American leaders about "bilateral ties and regional and international issues," according to Iran's official IRNA news agency.
The United States has urged Latin American countries not to deepen ties with Iran.
"As the regime feels increasing pressure, it is desperate for friends and flailing around in interesting places to find new friends," State Department spokeswoman Victoria Nuland said when asked about Ahmadinejad's trip.
Carlos Romero, a retired international relations professor at the Central University of Venezuela, said Ahmadinejad was "trying to find oxygen in Latin America," while links with other states continue to spiral downwards.
"His country is in a very complicated state internationally and is challenged internally by ever more protests on social networks," over the regime's denunciation of human rights at home and in Syria, Romero said.
While the international community and many neighboring states have condemned Syrian President Bashar al-Assad's months-long crackdown on protesters, ally Ahmadinejad has remained steadfastly loyal to the Damascus leadership.
The Iranian president will be accompanied on the Latin America trip by his ministers for foreign affairs, trade, commerce and mines and energy.
Ahmadinejad, who last came to Venezuela in November 2009, was scheduled to visit Caracas in September 2011 but the trip was postponed because of Chavez's cancer diagnosis. The Venezuelan leader, who has since declared himself free of the disease, last visited Iran in October 2010.
But the region's economic powerhouse, Brazil, is notably absent from Ahmadinejad's itinerary next week.
Lytton Guimaraes, an expert on Latin America at the University of Brasilia, said the omission indicated that President Dilma Rousseff was adopting a much cooler approach to Iran than that of her predecessor Luiz Inacio Lula da Silva.
"Brazil is not going to defend Iran, but nor will it attack it. It's going to sit still," Guimaraes told AFP.