Cooke was born at Grillagh, near Maghera, Co Derry, on 11 May 1788. The son of a tenant farmer, he was educated locally before entering Glasgow College in 1802, and was ordained a Presbyterian minister in 1808. He served at Duneane and then Donegore, Co Antrim; after his marriage in 1813, his presbytery allowed him to study further in Glasgow and in Dublin. In 1818, he was called to Killyleagh, Co Down.

More than anyone, Cooke led Ulster Presbyterianism away from the free-thinking radicalism which had spawned the United Irishmen's rising during his childhood. He gained prominence in 1821 by routing in debate a visiting English preacher, John Smethurst, who held Arian or Unitarian views. In 1824, Cooke was elected moderator of the Synod of Ulster.

By 1829, his oratorical command over the synod was such that the Arians, led by his rival Henry Montgomery, were forced to withdraw. In the same year, Cooke was called to a new church in May Street, Belfast, where he drew large congregations. In 1836, the synod made subscription to the Westminster Confession of Faith obligatory, and in 1840 it merged with the even more conservative Secession Synod to form the General Assembly of the Presbyterian Church in Ireland. Cooke was elected moderator in 1841 and again in 1862.

In defeating the Arians, Cooke had deliberately expelled political liberals; Montgomery's elder brothers had fought as United Irishmen. In 1834, Cooke addressed a mass rally of Protestants at Hillsborough, Co Down, forging a new alliance between Presbyterians and the established Church of Ireland to defend their interests against the newly emancipated Catholics. When Daniel O'Connell visited Belfast in 1841, Cooke staged a huge anti-Repeal rally.

He opposed the national system of undenominational schooling begun in 1831, and in 1840 won financial aid for Presbyterian schools. He also secured government support for a new Presbyterian College in Belfast, and became its president in 1847. He died in Belfast on 13 December 1868.

Statue in College Square East, Belfast.
Finlay Holmes, Henry Cooke (1981).