O'Brien is best known for his long career in the service of the English Crown, serving as a colonial governor in England's overseas possessions in Africa and the West Indies.

After being briefly imprisoned during the Second English Civil War, O'Brien eventually left England to enlist in the service of the French Royal Army in 1659 alongside his father.

[2] In 1648, O'Brien was briefly imprisoned by the Parliamentarian government in the Tower of London after his father defected to the Royalist side and took Lord Broghill's children as hostages in the ongoing Second English Civil War.

[1] Four years later in 1652, O'Brien paid a visit to Ireland and met the Lord Deputy Henry Cromwell, who noted that he had made the trip without prior authorisation from the Parliamentarian government in England.

[4][5] While he was governor, O'Brien "displayed little military capability"; in 1675, he dispatched a large force from the Tangier Garrison to launch a cattle raid against the Moors, which led to the English suffering 150 casualties.

[2] O'Brien was recalled to England and replaced as governor by Sir Palmes Fairborne in 1680 after failing to prevent the outer fortifications of English Tangier from being overrun by hostile local forces.

In the first months of 1689, O'Brien fought in Munster alongside the Protestant Boyle family (to whom he was related) against Irish Jacobite soldiers commanded by Richard Talbot, 1st Earl of Tyrconnell during the Williamite War in Ireland.

This was against King James II's wishes, but Webb speculated that McCarthy's actions may have been influenced by the fact that his father Donough MacCarty, 1st Earl of Clancarty and O'Brien were former comrades-in-arms.

In the meantime, O'Brien also formed an ad-hoc navy consisting of five newly outfitted sloops and a captured ship in order to counteract French maritime activity from the nearby colony of Saint-Domingue.

[11] This was resented by many Anglo-Jamaican merchants, a group of whom submitted a petition to the Board of Trade in concert with the Jamaican governor's council after his death to overturn this policy.

[12] Despite O'Brien being King William III's first choice to serve as governor of Jamaica, American historian Richard Slator Dunn noted that he was deeply unpopular among the Jamaican plantocracy.

[13] Taking this into consideration, the king appointed William Beeston, a wealthy planter who frequently served as a colonial agent in London (and had been one of the chief lobbyists for Jamaican interests in England) as the new governor of Jamaica.

[20] These claims were disputed by O'Brien's personal secretary, who argued that "the very men he delivered from the oppression of a former government... now strive to misrepresent his actions and asperse his memory".