The Middle American Research Institute was established at Tulane University in 1924.

The Middle American Research Institute seeks to study and safeguard the culture and history of the areas of Mesoamerica and lower Central America. The Institute supports education and research in archaeology, ethnography, ethnohistory, linguistics, and art history throughout Mexico and Central America. The Middle American Research Institute seeks to disseminate the results of its scholarship to academics, students, educators, and the public.

The Department of Middle American research started at Tulane in 1924 with William E. Gates as its director. Samuel Zemurray, president of the Cuyamel Fruit Company, generously donated $300,000 to “support the new Department of Middle American Research in the university, and supply money for an archaeological expedition.” Additionally, Zemurray bought Gates’ private library of original sources on the prehistory of Mexico and linguistics of the Maya area. At its beginning, the department was housed in a part of Dinwiddie Hall with a library containing 2,500 pieces, mostly from Gate's private collection. These texts would one day become the core of Tulane's Latin American Library. In 1925, Gates hired field archaeologist Frans Blom to lead the Department's first expedition into the Mexican hinterland. The report of the First Tulane Expedition, Tribes and Temples, became the Department's first publication. More staff hires included Ralph Roys, and Oliver La Farge.

Following disputes between members of the Department of Middle American Research and the president of Tulane, Frans Blom took over in the position of Director of the Department. In this position, Blom decided to promote “archaeology as the major function of the department.”

During Blom's time as director, he led multiple extensive expeditions to Latin America. In his own words, Blom describes the first expedition: “We discovered twenty-four ruined cities hitherto unrecorded by scientists… To sum up the matter in a few words, the work that we have begun in Central America will put Tulane University on the map as having the greatest department in the country on Maya Indian study.” Throughout his time with the Department, Blom participated in four major expeditions covering areas and topics including Guatemalan ancestral ritual calendars, investigations of Mayan ritual cycles at Jacaltenango, and a long trek from the southern coast of Chiapas to Chichen Itza on the Yucatán. Tulane's location in New Orleans (a major port city servicing Latin America) meant that the Department was often frequented by researchers on their way into the field.

The Department of Middle American Research became known internationally when reproductions of architecture from the Nunnery Quadrangle at Uxmal, discovered during the Institute's expeditions, were displayed at the World's Fair of 1933. These early expeditions account for most of the Institute's current anthropological collections.

In 1938 the Department of Middle American Research was renamed the Middle American Research Institute. Blom's career at the Institute lasted until he was asked to resign for health reasons in November 1941.

Robert Wauchope taught archaeology at the University of Georgia and then directed the Laboratory of Anthropology and Archaeology at the University of North Carolina-Chapel Hill. Following World War II, Wauchope came to the Middle American Research Institute to pursue his research at Zacualpa in the Guatemalan highlands. During Wauchope's time as director, the Institute became increasingly integrated with Tulane. Researchers took roles as professors, and projects spanned multiple departments within the university. Wauchope was praised for his “revitalization of the Middle American Research Institute in less than a decade.”