He was born in Connecticut and became a doctor in 1819. He then settled in Upper Canada, and in 1824 he established the first medical school in Upper Canada, in St. Thomas, under the patronage of Colonel Thomas Talbot. In 1828 he was elected to the Legislative Assembly as a representative for London. He was originally a Reformer in the same vein as Robert Baldwin, but was attracted by William Lyon Mackenzie's more radical reform movement. In 1836 he travelled to Britain to argue the case for reform in Canada, but he was unsuccessful.
In December of 1837, Duncombe heard reports of Mackenzie's rebellion in Toronto. Duncombe, with Robert Alway, Finlay Malcolm, Eliakim Malcolm, and Joshua Doan, gathered about 200 men on December 8 and marched towards Toronto. This is sometimes known as the Western Rising. A few hundred more rebels joined them on their march, but they dispersed near Hamilton on December 13 when they learned of Mackenzie's defeat, and that a militia under Colonel Allan MacNab was on their way to stop them. Duncombe and Eliakim Malcolm fled to the United States; Duncombe remained there for the rest of his life, despite being pardoned in 1843. Joshua Doan was executed in 1839.
Duncombe's parliamentary career began in 1685, when he was elected member of parliament for Hedon, and he was afterwards one of the representatives of Yarmouth in the Isle of Wight and of Downton in Wiltshire.
A celebrated member of the Duncombe family was Thomas Slingsby Duncombe (1796-1861), a Radical politician, who was member of parliament for Hertford from 1826 to 1832 and for Finsbury from 1834 until his death.
Duncombe defended Lord Durham's administration of Canada; he sought to obtain the release of John Frost and other Chartists, whose immense petition he presented to parliament in 1842; and he interested himself in the affairs of Charles II., the deposed duke of Brunswick.
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