The town was a township of the former Central New York Military Tract. Manlius is the name of several important Romans, but exactly which one was being honored is no longer known. The current town was first settled around 1790.
The Town of Manlius was created in 1794, along with Onondaga County, as a much larger entity, which was decreased by the formation, in part or in whole, of new towns (DeWitt, Onondaga, Salina) and part of Syracuse. It was bounded north by the township of Cicero, east by the Oneida Reservation, south by Pompey, and west by Onondaga Creek and Lake, including all the Onondaga Salt Springs Reservation north of the old Genesee Road and east of Onondaga Creek, comprising all the present towns of Manlius, DeWitt, part of Onondaga, and part of Salina, as laid out in 1809. It was reduced to its present limits in 1835. The economy related to trade generated by the Erie Canal contributed to the early development of the town.