Shortly after her birth (1242), Margaret was betrothed to Albert "the Degenerate", eldest son and heir of Henry III "the Illustrious", Margrave of Meissen. The marriage took place in June 1255, the bride receiving Pleissnerland (the towns of Altenburg, Zwickau, Chemnitz and Leisnig) as her dowry.
The couple settled at his residence in Eckartsberga and later moved to Wartburg, where she bore five children: three sons (Henry, Frederick and Dietzmann) and two daughters (Margaret and Agnes). Through her second son Frederick – later Margrave of Meissen – Margaret was the direct ancestor of the Electors and Kings of Saxony and English Queen consorts Margaret of Anjou and Anne of Cleves.
In 1265 her husband received the titles of Landgrave of Thuringia and Count Palatine of Saxony (German: Pfalzgräf von Sachsen) after the abdication of his father, who retained control of Meissen.
After the execution of her nephew Conradin (29 October 1268), Margaret, as the next legitimate relative, became the rightful Queen of Sicily and the general heiress of the Hohenstaufen claims over the Duchy of Swabia and the Kingdom of Jerusalem (despite the fact she was not descended from the Kings of Jerusalem, her father Frederick II had claimed the kingdom for himself). Her son Frederick assumed by some time this titles on her right.
After discovering the adultery of her husband with Kunigunde of Eisenberg, Margaret left Wartburg; according to a legend, before her departure she bit her son Frederick in the cheek; he was called henceforth Frederick the Bitten (de: Friedrich der Gebissene). The flight took place on 24 June 1270. Margaret went to Frankfurt-am-Main and was supported there by the citizens. She died there six weeks later.