In 1665 the Plague was raging in London. A taylor from Eyam by the name of George Viccars ordered some cloth from the capital and it arrived damp and had to be laid out to dry. This released the plague carrying fleas and within days, Viccars fell ill and died. Several of his neighbours also died and some families began to panic and fled the area. William Mompesson, the rector, supported by Thomas Stanley, a former incumbent, feared that this would spread the disease over a wider area and asked villagers to quarantine themselves.

Food and medical supplies were left at various points on the village boundary. Eyam church was closed and services were held in Cucklett Delf, a valley nearby where a Plague Commemorative Service is still held annually. There were no funerals and families buried their own dead near their homes. At nearby Riley a Mrs Hancock buried her husband and 6 children in a space of 8 days. The Riley graves, as they are known, are still there. The Plague ended in October 1666 and had claimed 260 lives in an 18 month period. Some of the cottages now carry a commemorative plaque.

The churchyard contains various interesting tombstones and monuments including ones to Thomas Stanley and Catherine Mompesson, the wife of William. She had stayed in the village with her husband and died of the plague in its later stages. It also contains a magnificent Celtic Cross, one of the finest in the country and probably a wayside preaching cross from the 8th century. Most of the bodies were buried in the gardens and fields.