In 1665 plague hit England, and a consignment of cloth bound for his village brought with it the infectious fleas which spread the disease. After an initial flurry of deaths in the autumn of that year it died down during the winter only to come back even more virulently in the spring of 1666. Mompesson, in conjunction with another clergyman, the ejected Puritan, Thomas Stanley, took the courageous decision to isolate the village. In all, 260 of the village's inhabitants, including his wife Catherine, died before the plague claimed its last victim in December 1666. Mompesson became associated with the plague and was not universally welcomed at his next parish, Eakring, Nottinghamshire. In 1670 he remarried, his second wife being a widow, Elizabeth Newby. She was a relative of his patron, Sir George Saville, and through his patronage Mompesson eventually became Prebendary of Southwell, Nottinghamshire, although he declined the opportunity to be Dean of Lincoln Cathedral. He died in 1709.