Maria Luisa, her brother Ferdinand and her sister Isabella are traditionally said to have been educated by Étienne Bonnot de Condillac, a well-known French philosopher.

Her husband was the son and heir of the widowed Charles III of Spain, previously Duke of Parma and King of Naples and Sicily.

"[2] Her father-in-law Charles III viewed her to be frivolous and attempted to control and supervise her private life and restrict her personal freedom, but with little success.

Her father-in-law took care to remove both Charles and Maria Luisa from interfering in state affairs; however, while her husband was of a passive character and devoted to his interests in hunt and mechanics, Maria Luisa was interested in state affairs and, being the dominant partner of the two, became the leading figure in the circle of opposition which gathered around the heir to the throne.

On the first meeting between Charles IV and his ministers, Maria Luisa was present, a step which attracted attention and which became the rule during the reign of her spouse.

The Queen's confessor Fray Juan Almaraz wrote in his last will that she admitted in articulo mortis that "none, none of her sons and daughters, none was of the legitimate marriage".

There is no doubt that Maria Luisa and Godoy had a close relationship regardless of the nature of it, as their correspondence illustrates that she spoke to him of such intimate matters as the discontinuation of her menstruation and the depression caused by her menopause, and was given comfort by him and assured that she would find her new state in life fulfilling as well.

The Queen's purported relationship with prime minister Godoy in combination with her reputed political influence exposed her to the public's discontent over Godoy's Treaty with Napoleonic France, in which French troops were stationed in Spain, and in one incident, the Queen was threatened by a mob and had to be protected by her life guard.

On 19 March 1808, Charles IV abdicated the throne in favor of his son Ferdinand VII due to pressure from Napoleon I.

In April 1808, Maria Luisa accompanied Charles IV and Manuel Godoy to a meeting with Napoleon in Bayonne in France to persuade the emperor to intercede and assist her husband in reclaiming the Spanish throne from their son.

At the meeting, however, Napoleon forced both Charles IV and Ferdinand VII to renounce their claims to the throne in favor of his brother Joseph Bonaparte and declared the Bourbon dynasty in Spain deposed.

After the forced abdication, Maria Luisa lived with Charles IV and Manuel Godoy as state prisoners of Napoleon in France.

During their residence in Rome, Maria Luisa and Charles created a large art collection of paintings by artists Titian, Correggio, Leonardo, Lucas Cranach, Andrea del Sarto, Parmigianino, Bronzino, Palma El Viejo, Tintoretto, Veronese, Poussin, Gaspar Dughet, and Alessandro Turchi.