Colonel Joel Stone, who served with Loyalist militia during the American Revolutionary War, established a settlement on this site in 1789.

During the War of 1812, American forces raided the government depot in the town to disrupt the flow of British supplies between Kingston and Montreal.

Gananoque lies directly on three of Canada's busiest transportation routes: the four-lane Highway 401, the double-track Canadian National Railway main line, and the St. Lawrence Seaway.

Via Rail inter-city passenger trains bound for Toronto and Ottawa stop at the unstaffed Gananoque station to the north of downtown.

In 1830, water was diverted near Newboro to the Cataraqui River as part of the Rideau Canal, sending this traffic instead to Kingston.

A four-mile short line railroad once linked the main CN Rail tracks to the heart of the village; the Thousand Islands Railway terminated near the town hall.