She was the daughter of Sir John Wake, from whom she inherited the title, 'Lady Wake of Liddel. Her mother was Joan de Fiennes, making her a cousin of Roger Mortimer, 1st Earl of March.

Margaret married John Comyn, son of the John Comyn who was murdered by Robert the Bruce in 1306. Her husband John died at Bannockburn, and their only child, Aymer Comyn, died a toddler in 1316. She married for a second time to Edmund of Woodstock, 1st Earl of Kent, they having received a dispensation in October 1325, with the wedding being celebrated probably at Christmas.

Through her marriage to Edmund (who was executed for treason in 1330), she was the mother of two short-lived Earls of Kent and of Joan of Kent (wife of the Black Prince). The pregnant Margaret and her children were confined to Salisbury Castle, and her brother Thomas Wake was accused of treason but later pardoned. When King Edward III of England reached his majority and overthrew the regents, he took in Margaret and her children and treated them as his own family. Margaret died during an outbreak of the plague.