Although a Protestant country-gentleman, O’Brien supports Catholic Emancipation while remaining a supporter of British-Irish union. In 1843, in protest against the imprisonment of Daniel O’Connell, he joins O’Connell’s anti-union Repeal Association.
Three years later, O’Brien withdraws the Young Irelanders from the association. In January 1847, along with Thomas Francis Meagher, he founds the Irish Confederation, although he continues to preach reconciliation until O’Connell’s death in May 1847. He is active in seeking relief from the hardships of the famine. In March 1848, he speaks out in favour of a National Guard and tries to incite a national rebellion. He is tried for sedition on May 15, 1848 but is not convicted.
On July 29, 1848, O’Brien and other Young Irelanders lead landlords and tenants in a rising in three counties, with an almost bloodless battle against police at Ballingarry, County Tipperary. In O’Brien’s subsequent trial, the jury finds him guilty of high treason. He is sentenced to be hanged, drawn, and quartered. Petitions for clemency are signed by 70,000 people in Ireland and 10,000 people in England.
In Dublin on June 5, 1849, the sentences of O’Brien and other members of the Irish Confederation are commuted to transportation for life to Van Diemen’s Land, which is Tasmania in present-day Australia.
O’Brien attempts to escape from Maria Island off Tasmania, but is betrayed by Captain Ellis of the schooner hired for the escape. He is sent to Port Arthur where he meets up with John Mitchel, who had been transported prior to the rebellion. The cottages which O’Brien lives in on Maria Island and Port Arthur have been preserved in their 19th century state as memorials.
Having emigrated to the United States, Ellis is tried by another Young Irelanders leader, Terence MacManus, at a lynch court in San Francisco for the betrayal of O’Brien. He is freed for lack of evidence.
In 1854, after five years in Tasmania, O’Brien is released on the condition he never return to Ireland. He settles in Brussels. In May 1856, he is granted an unconditional pardon and returns to Ireland that July. He contributes to The Nation newspaper, but plays no further part in politics.