The location making up East Syracuse has been a hotbed of activity since before its incorporation in 1881. Sections of its main road, James Street, were part of an important trail that led the Onondaga people to their capital along the northeast shore of Onondaga lake. The main line of the New York Central Railroad went through the village when it was previously known as Messina. From the railroad to the Erie Canal, much commerce and trade went through East Syracuse.

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Nowadays, East Syracuse is home to Bristol Laboratories, formerly Cheplin Laboratories, which are part of Bristol-Myers-Squibb. Manlius Street, sometimes referred to by residents as Main Street, is home to a variety of locally-owned shops, restaurants, bars, manufacturers and other service providers. Residents enjoy the local flavor of the village, along with easy access to many fun outdoor parks and amenities.

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