From 1978 to 1982 he directed excavations at the Templo Mayor, the remains of a major Aztec pyramid in central Mexico City.

1987 saw the creation of the Urban Archaeology Program (directed by Matos) in which excavations in downtown Mexico City were expanded beyond the immediate site of the Templo Mayor.

In addition to his work at the Templo Mayor and its museum, Matos Moctezuma has held many important posts in the field of Mexican archaeology.

The most notable is election to the Colegio Nacional, a prestigious group of the top scholars and artists in Mexico.

In 2017, the Eduardo Matos Moctezuma Lecture Series at Harvard University were announced.