In 1761, O’Brien enters the Irish House of Commons as the member for Ennis, sitting until 1768. Subsequently he successfully runs for Clare, a seat previously held by his father, holding it until 1776. He is then again elected for Ennis, but following the unseating of Hugh Dillon Massy as Member of Parliament for Clare, he returns to represent that constituency in 1778. In the election of 1783, he becomes the representative for Tuam. He is sworn of the Privy Council of Ireland in 1786. He serves for the latter constituency until 1790, when he is re-elected for Ennis. He holds this seat finally until his death on January 15, 1795.
O’Brien marries Anne French, the daughter of Robert French, in 1768 and has by her seven children, three sons and four daughters. He is succeeded in the baronetcy as well as in the constituency of Ennis by his oldest son Edward.
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, 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 (Tasmania in present-day Australia).
O’Brien attempts to escape from Maria Island off Tasmania but is betrayed by the captain of the schooner hired for the escape. He is sent to Port Arthur where he meets up with John Mitchel.
O’Brien is a founding member of the Ossianic Society, which is founded in Dublin on St. Patrick’s Day 1853, whose aim is to further the interests of the Irish language and to publish and translate literature relating to the Fianna. He writes to his son Edward from Van Diemen’s Land, urging him to learn the Irish language. He himself studies the language and uses an Irish-language Bible and presents to the Royal Irish Academy Irish-language manuscripts he has collected.
In 1854, after five years in Tasmania, O’Brien is released on the condition he never returns 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.
In 1864 he visits England and Wales, with the view of rallying his failing health, but no improvement takes place, and he dies at Bangor, in Wales on June 16, 1864.
A statue of William Smith O’Brien stands in O’Connell Street, Dublin. Sculpted in Portland limestone, it is designed by Thomas Farrell and erected in D’Olier Street, Dublin, in 1870. It is moved to its present position in 1929.