He was born in County Meath, eldest of the ten children of Patrick Cusacke of Ballymolghan and his wife Maud Plunkett, daughter of Thomas Plunkett of Loch Gabhair (Lagore), Ratoath.
They had five children, including Robert, who inherited his father's estate and sat in the Irish House of Commons as MP for Kells in 1640–1642, and Anne, who married Richard Barry.
John himself, though he conformed outwardly to the Protestant faith, was deeply sympathetic to Roman Catholics, and was an active member of Saint Anne's Guild, the leading Catholic guild in Dublin, helping to defend its charter when it was under threat.
He served four terms as one of the masters of the Dublin Merchants' Guild, and on its behalf, he petitioned the English Crown in 1609 for repayment of loans owing to the Irish Exchequer: he claimed that £1300 was owed to him personally, an indication of his wealth.
He was the grandfather of two distinguished judges: Robert, his eldest son, was the father of Adam Cusack, justice of the Court of Common Pleas (Ireland), and his daughter Anne was the mother of James Barry, 1st Baron Barry of Santry, Lord Chief Justice of Ireland.