Margaret was born in 1556 at York to the Middleton family (her father Thomas Middleton was sheriff of York in 1564–1565).
In 1571, at the age of 15, Margaret married John Clitherow — a York butcher and Anglican, widower with two children.
Around 1574, at the age of 18, Margaret converted to Catholicism. Her conversion initiated her 12-year Catholic-recusant ministry — systematically sheltering and hiding Catholic recusant priests in the Clitherow townhouse at The Shambles in York, undertaking the secret Catholic Masses and sacraments in her household, and undertaking the personal education of her children (son Henry became a Catholic priest) in the Catholic faith.
Margaret was repeatedly imprisoned for recusancy — her longest imprisonment being 20 months at York Castle.
On March 10, 1586, Margaret was arrested during a search of her Shambles townhouse — the search that discovered the hidden Catholic priest-hole and the Catholic liturgical vestments and vessels concealed within.
Charged with harboring Catholic priests and the recusant offense, Margaret refused to plead — specifically to prevent her children from being forced to testify against her.
Under English common law, refusal to plead provoked the execution method of peine forte et dure ('strong and hard punishment') — being pressed to death under heavy weights.
On March 25, 1586 (Good Friday and the Feast of the Annunciation), Margaret was pressed to death at the Ouse Bridge in York — under 700–800 pounds of weight. Her last words were: 'Jesu! Jesu! Jesu! Have mercy on me!'
Margaret was pregnant with her fifth child at the time of the execution. She died at approximately the age of 30.
Canonized on October 25, 1970 by Pope St. Paul VI as one of the Forty Martyrs of England and Wales.