Both Henry and his twin Thomas were schooled locally by the rector of Llangattock (Crickhowell), the Rev. Matthew Herbert. This occupied six years preceding their attendance at Jesus College, Oxford, in 1638. However, around 1640, Vaughan's family influenced him to pursue a career in law, and he abandoned his degree course at Oxford.
As the Civil War developed, he was recalled home from London, initially to serve as a secretary to Sir Marmaduke Lloyd, a chief justice on the Brecknockshire circuit and staunch royalist. Vaughan is thought to have served briefly in the Royalist army and, upon his return, began to practise medicine. By 1646, he had married Catherine Wise, with whom he reared a son, Thomas, and three daughters, Lucy, Frances, and Catherine. After his first wife's death, he married her sister, Elizabeth.
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