The skulls may also shatter existing notions about the ancient culture of the area, 'LiveScience' reported.
The discovery was made in an otherwise empty field that once held a vast lake, but was miles from the nearest major city of the day, said study co-author Christopher Morehart, an archaeologist at Georgia State University.
"It's absolutely remarkable to think about this little nothing on the landscape having potentially evidence of the largest mass human sacrifice in ancient Meso-America," Morehart said.
Researchers led by Morehart were using satellite imagery to map ancient canals, irrigation channels and lakes that used to surround the kingdom of Teotihuacan - home to the Pyramid of the Sun, about 50 kilometers from Mexico City. The vast ancient kingdom flourished from around AD 200 to 650.
Morehart stumbled upon a site with evidence of looting in a now drained lake called Lake Xaltocan.
The team discovered lines of human skulls with just one or two vertebra attached. To date, more than 150 skulls have been discovered there.
The site also contained a shrine with incense burners, water-deity figurines and agricultural pottery, such as corncob depictions, suggesting a ritual purpose tied to local farming.
Carbon dating suggested that the skulls were at least 1,100 years old, and the few dozen analysed so far are mostly from men, Morehart said.
The findings shake up existing notions of the culture of the day, because the site is not associated with Teotihuacan or other regional powers, said Destiny Crider, archaeologist at Luther College in Iowa.
Human sacrifice was practised throughout the region, both at Teotihuacan and in the later Aztec Empire, but most of those rituals happened at great pyramids within cities and were tied to state powers.
By contrast, "this one is a big event in a little place," Crider said.
The shrines and the fact that sacrifice victims were mostly male suggest they were carefully chosen, not simply the result of indiscriminate slaughter of a whole village, Crider said.