Mary Henrietta Stuart was born at St. James's Palace, London. Charles I designated her Princess Royal in 1642, thus establishing the tradition that the eldest daughther of the British Sovereign might bear this title. The title came into being when Queen Henrietta Maria, the daughter of King Henri IV of France wished to imitate the way the eldest daughter of the French king was styled (Madame Royale). Until that time, the eldest daughters of English and Scottish kings were variously titled Lady or Princess (The younger daughters of British Sovereigns were not consistently titled princesses of Great Britain and styled Royal Highness until the ascension of George I in 1714).
Her father wished the Princess Royal to marry a son of Philip IV, king of Spain, while her cousin, the Elector Palatine Karl Ludwig, was also a suitor for her hand. Both proposals fell through and she was bethrothed to Willem, the son and heir of Frederick Henry, Prince of Orange-Nassau and Stadholder of the United Provinces, and of Amalia of Solms-Braunfels. The marriage took place on 2 May 1641 at the Chapel Royal, Whitehall Palace, London, but was not consumated for several years due to the bride's young age. However,in 1642, Mary crossed over to Holland with her mother, Queen Henrietta Maria, and in 1644, as the daughter-in-law of the stadtholder, she began to take her place in public life.
In March 1647, her husband, Willem II, succeeded his father as stadholder. However, in November 1650, just after his attempt to recapture Amsterdam from the Spanish, he died of smallpox. The couple's only child, Willem (later William III), was born a few days later. The Dowager Princess of Orange was obliged to share the guardianship of her infant son, with his grandmother Amelia, the widow of Frederick Henry, and with Frederick William, the elector of Brandenburg. She was unpopular with the Dutch due to her sympathies with her family, the Stuarts; and at length, public opinion having been further angered by the hospitality that she showed to her brothers, the exiled Charles II and the Duke of York (later James II), she was forbidden to receive her relatives. From 1654 to 1657, the princess passed most of her time away from Holland. In 1657 she became regent on behalf of her son for the principality of Orange, but the difficulties of her position led her to implore the assistance of King Louis XIV of France; the French king answered by seizing Orange himself.
The restoration of Charles II in Britain, greatly enhanced the position of the Dowager Princess and her son in Holland. In September 1660, she returned to England. She died of smallpox at Whitehall Palace, London and was bured in Westminster Abbey.