He was born in Spencertown, New York in 1782. After his mother died, he was taken into a foster home; his foster father was a tanner. He ran away from home in 1799 and joined his brother Seneca, who was farming north of York (Toronto) in Upper Canada. At the beginning of the War of 1812, he purchased a tannery from a recent immigrant from the United States who had decided to return there after war was declared. Ketchum joined the local militia, but his loyalty was called into question after York was temporarily held by the Americans. After the war, he helped fund the rebuilding of the bridges over the Don River and also contributed to the building of the first common school at York. He taught Sunday school at the Methodist church, which he helped to establish in the area. He opposed the exclusive control of the clergy reserves by the Anglican church and was known as an opponent of the Family Compact. In 1828, he was elected to represent York in the 10th Parliament of Upper Canada; he was reelected in 1830 but did not run again in 1834. Although he had supported William Lyon Mackenzie in the assembly, he did not take part in the Upper Canada Rebellion.
Shortly after the rebellion, he relocated his tannery to Buffalo, New York, although he continued to live in Toronto. In 1845, he moved to Buffalo, leaving his property in Toronto to his children from his first wife. He continued to be a generous benefactor to the community there until his death in 1867. Ketchum contributed to churches and schools in Buffalo. Ketchum Hall at Buffalo State College was named in his honour, as is Ketchum Street on the city's Lower West Side. Jesse Ketchum School in Toronto is also named in his honour.