O'Brien was the eldest son of William O'Brien, 3rd Earl of Inchiquin, and his wife, Mary (née Villiers), sister of the 1st Earl of Jersey, and inherited his father's titles in 1719.

Inchiquin was Whig Member of Parliament for Windsor from 1722 to 1727, for Tamworth from 1727 to 1734, for Camelford from 1741 to 1747 and for Aylesbury from 1747 to 1754.

From 1744 to 1751, he was a Lord of the Bedchamber to Frederick, Prince of Wales, and admitted to the Privy Council of Ireland in 1753.

[1] On his death in 1777, without surviving male heirs, his titles passed to his nephew, Murrough O'Brien, who was later created Marquess of Thomond.

They had five children: He married, secondly, Mary Moore, daughter of Stephen Moore, 1st Viscount Mount Cashell and Alicia Colville, on 12 October 1761 Additionally, Inchiquin was feted by antiquarians and many of the works of Irish history produced at this time are dedicated to him; as an Anglican deriving his lineage from an old Gaelic family, he was a politique choice for those wishing to disseminate their work in Ascendancy Ireland and Hanoverian Britain.