The city’s strategic location at a river junction was the site of the chief village of the Miami people. The village and location drew the French, who built a fortified trading post there in the early 1700s. Control of the site was contested by the British and the French, until it was taken by the British in 1760. Modern Fort Wayne grew from a fort that was established in 1794 by General Anthony Wayne, who had defeated the Miami after they resisted white intrusion, thus opening the area to white settlement. Fort Wayne incorporated as a city in 1840.

Industry grew after construction of the Wabash-Erie Canal was completed in 1840 and the arrival of the railroad in the mid-1850s. In the 1920s the city emerged as a financial center with the growth of regionally important banks and insurance companies. Over the years Fort Wayne has carried several nicknames; in 1982 a new one was added when townspeople worked through several days building sandbag barriers to protect the city against floodwaters, becoming the "the city that saved itself."

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