He subsequently embarked on a career as a privateer, being recorded in October 1589 as the captain of the Elizabeth and Mary, a ship owned by his cousin, the London merchant Thomas Myddelton, which sailed into Plymouth with a captured Brazilian.
In 1590 he sailed another of his cousin's ships, the Riall, capturing two argosies bound for Lisbon from Florence, with a cargo worth £13,000.
Midleton's privateering career is perhaps reflected in a claim in a Welsh manuscript owned by Thomas Pennant that Midleton and two companions (one of them being Thomas Prys, another Welsh poet and privateer) were 'the first that smoaked Tobacco publickly at London'.
Whilst anchored at the island of Escudo, not inhabited but full of Tarrtasis and Aligators', Midleton completed his Welsh metrical version of the psalms on 24 January 1596.
[citation needed] Midleton's metrical Welsh version of some of the psalms, entitled Rhann o Psalmae Dauyd, a Phrophwyti eraill, was probably published in 1595 before his departure for Panama.