The prince, joined by Social Development Minister Maria Fernanda Villegas, was all smiles and appeared relaxed with the little ones at the Friends of Jesus children's facility.
It was the second visit the prince made to a children's center on this visit, after meeting young people at a shelter on June 27.
Prince Harry did not seem limited by the language barrier in meeting and playing with the youngsters with a range of disabilities and disorders.
Harry, an army captain who is fourth in line to the British throne, arrived in Santiago after a stop in Brazil to watch the England football team play out a 0-0 bore draw against Costa Rica in its last game of a disappointing tournament.
By Ruchi Singh