At the age of fifteen he entered Emmanuel College, Cambridge, gaining his BA in 1624-5 and his MA in 1628.

His great work, the Lexicon Heptaglotton Hebraicum, Chaldaicum, Syriacum, Samaritanum, Aethiopicum, Arabicum, et Persicum (1669), took him eighteen years to complete, working (according to his own account) from sixteen to eighteen hours a day.

He employed fourteen assistants on the project, and spent £12,000, ruining himself in the process as there was little demand for his finished lexicon.

[2] By 1667, he found himself in prison because he was unable to discharge his brother's debts, for which he had made himself liable.

Before undertaking the Lexicon Heptaglotton, Castell had helped Dr Brian Walton in the preparation of his Polyglott Bible.