O’Brien is the son of Sir Edward O’Brien, 2nd Baronet and his wife Mary Hickman, inheriting the baronetcy upon the death of his father in 1765. He is educated at Trinity College, Dublin and enters the Middle Temple in 1753, later becoming a barrister.
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 is elected a Fellow of the Royal Society in 1773.
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.