Onondaga, geographically at the centre of the five Haudenosaunee (Iroquois) nations, were designated "firekeepers" of the Iroquois league, serving as moderators at councils and retaining the wampum records of the confederacy. Thadodaho, the most celebrated title among the 50 confederacy chiefs, was held by an Onondaga. Despite this central position in the confederacy, they often pursued an independent policy, as in 1649 when they remained neutral while the Seneca and Mohawk defeated the Huron-Wendat. The main Onondaga town, as "capital" of the Haudenosaunee Confederacy, was a hub of frontier diplomacy for two centuries.

The Onondaga themselves burned their town when an army under Frontenac invaded their country in 1696. The village was also burned by Americans during the American Revolution. After the war a portion of the Onondaga immigrated with other Iroquois to lands in Canada on the Grand River in 1785. They did not increase as rapidly as other groups on the Six Nations Reserve.

Today, after the inclusion of the Tuscarora nation early in the 18th century, the Haudenosaunee, or Iroquois Confederacy or Six Nations, comprise the Tuscarora, Haudenosaunee, Mohawk, Oneida, Cayuga, Seneca, and Onondaga Nations. By 1996 the Onondaga numbered only 1127 and their registered population in 2012 was 754. Another portion of Onondaga retain lands in their ancestral homeland, outside Syracuse, New York.

See also Aboriginal People: Eastern Woodlands and general articles under Aboriginal People.