Mitchel was born at Camnish, near Dungiven, Co Londonderry, on 3 November 1815. The son of a Unitarian minister and United Irishman, he was educated at Trinity College, Dublin, before entering a solicitor's office in Newry, Co Down. He later practised in Banbridge, Co Down. In 1836, he eloped to England with sixteen-year old Jane Verner, but was brought back in custody; they eloped again in 1837 and were married.

Mitchel began writing for The Nation, and when Thomas Davis died in 1845, Charles Gavan Duffy invited Mitchel to join the newspaper. He subsequently wrote masterly descriptions of the potato famine, contributed a life of Hugh O'Neill to The Library of Ireland, and edited the poems of Davis and James Clarence Mangan. In 1846, Mitchel and other Young Irelanders broke with Daniel O'Connell, rejecting the doctrine of 'moral force', and founded the Irish Confederation.

More impatient than Duffy, Mitchel soon left The Nation and the Confederation, and in February 1848 published the first issue of The United Irishman. It openly preached sedition to 'that numerous and respectable class of the community, the men of no property', and in May 1848 Mitchel was convicted of treason felony and sentenced to fourteen years' transportation. He hoped his sentence would provoke an insurrection, but nothing more than a skirmish in Co Tipperary ensued.

Sent to Van Diemen's Land (now Tasmania), Mitchel escaped in 1853 to America, where he published his famous Jail Journal. In one entry, he welcomes the Crimean War believing an Irish rebellion can succeed only if England is preoccupied elsewhere. The sentiment influenced Patrick Pearse in 1916.

Mitchel launched several newspapers in America, and as editor of the Richmond Examiner championed slavery; he was imprisoned for several months after the Civil War ended. In 1867, he founded the Irish Citizen in New York, but angered Fenians by suggesting they should give allegiance to their new country. In 1875, he was returned unopposed as MP for Tipperary, but was disqualified as a convicted felon. Returning to Ireland, he was again elected, but died at Dromalane, Newry, on 20 March 1875 before he could be unseated.