O'Brien was the son of Donogh O'Brien, 4th Earl of Thomond and Elisabeth FitzGerald. On 13 July 1608 he married Mary Brereton, daughter of William Brereton, 1st Baron Brereton and Margaret Savage, and together they had 5 daughters:
Lady Margaret O'Brien, who married firstly Edward Somerset, 2nd Marquess of Worcester and secondly Donough Kearney
Lady Mary O'Brien (d. 1686) married, on 24 June 1627, Charles Cokayne, 1st Viscount Cullen
Lady Elisabeth O'Brien (d. 1656–1659) married, on 21 August 1636, Dutton Gerard, 3rd Baron Gerard (1613–1640), grandson of Thomas Gerard, 1st Baron Gerard
Lady Anne O'Brien (d. 1645) married, in 1641, Henry O'Brien, 7th Earl of Thomond
Lady Honora O'Brien