Clinton's trip begins in Uruguay, where she was representing the United States at the inauguration of President Jose Mujica.
She left her original itinerary intact, still planning to go to Santiago to meet with Chilean President Michelle Bachelet, who hands the country's reins of power to Sebastian Pinera in about a week.
Clinton is expected to outline U.S. offers of aid for quake relief. Officials said more than 700 people died in the 8.8-magnitude earthquake and shook Chile on Saturday. About 2 million people in Chile are said to have been affected by the quake.
However, her visit to Santiago will be shorter than planned, a change that allowed Clinton to fit in a side trip to Buenos Aires where she will meet with Argentine President Cristina Fernandez.
Clinton is also to travel to Brazil and a meeting with President Luiz Inacio Lula da Silva, who has an international trip of his own coming up. He is to go to Iran to discuss bilateral issues but the United States hopes he can convince Tehran to become more open about its nuclear ambitions.
Clinton is also to stop in Costa Rica and Guatemala before returning Friday to Washington.