Married to Mary's brother, Francesco II d'Este Duke of Modena, she was widowed after only two years. Her husband died of gout and severe arthritis; the pain of these conditions could explain why the couple had no children.
Margherita Maria returned home to Parma and was soon faced with the death of her father, Ranuccio II Farnese Duke of Parma. Her mother had died when she was not quite two. Her only full sister was a Benedictine nun. Her only full brother died while she was in Modena (leaving behind an infant daughter, Elizabeth Farnese, who would marry King Philip IV of Spain).
She lived the rest of her life subject to her much younger half-brother Francesco, the new Duke of Parma, who had quickly married Margherita Maria's late brother's widow so that he wouldn't have to return the dowry. For the next 24 years, she remained in the bosom of her family, passing away at their summer palace in Colorno at the age of 53.