Philip V of Spain, a French prince, was recently crowned King of Spain upon the death of childless Charles II. In order to enforce his shaky authority over Spain due to his French birth, Philip V decided to maintain ties with Victor Amadeus II, Duke of Savoy. Philip V's brother, Louis, Duke of Burgundy, had married the elder sister of Maria Luisa several years earlier, and in mid-1701, Philip V asked for Maria Luisa's hand with the permission of his grandfather Louis XIV.
Maria Luisa was wed by proxy to Philip V on 12 September 1701 at the age of barely thirteen and was escorted to Nice, arriving there on 18 September. While in Nice, she was greeted by Pope Clement XI who gave her the Golden Rose on 20 September as a ritualistic gift for the young princess. Within a week, she sailed from Nice for Antibes and was taken to Barcelona. The official wedding took place on 2 November 1701.
Philip V was deeply in love with her from the start: as would be the case of his next consort, he was sexually dependent on her, as his religious scruples prevented him from exercising any sexual life outside of marriage. She was also said to be very beautiful and intelligent. Unlike what was normal for a Spanish monarch, he usually slept in her bed the entire night, and insisted upon his conjugal rights. Already shortly after their marriage, the French ambassador, the Duke of Gramont reported to Philip’s grandfather, Louis XIV, that Philip would be completely governed by his spouse as long as he had one, a report that led Louis XIV to warn him not to allow his queen to dominate him. Marie Luisa is described as remarkably mature for her age, politically savvy, articulate and hardworking, and she has been credited with giving the normally passive Philip V the energy he needed to participate in warfare.
In 1702, Philip V was obliged to leave Spain to fight in Naples as part of the ongoing War of Spanish Succession. During her husband's absence, Maria Luisa acted as Regent from Madrid. She was praised as an effective ruler.Despite being only fourteen at that time, Maria Luisa's effective regency made her admired in Madrid and throughout Spain.
Maria Luisa gave birth to the couple's first child, Infante Luis Felipe in 1707. Maria Luisa gave birth to three more children, two of whom would survive infancy. Towards the end of her life, the Queen became ill. She would die from the effects of tuberculosis on 14 February 1714.