In 1729 at the age 18, Barbara married the future Ferdinand VI of Spain, two years her junior. Her brother Joseph married Ferdinand's half-sister, the Spanish Infanta Mariana Victoria, who had been rejected as a bride for Louis XV. The double marriage was meant to repair the Portuguese-Spanish alliance.
During their time as Prince and Princess of the Asturias, Ferdinand and Barbara became the target of the opposition known as the Spanish party, in parallel with Spain's deteriorating relations with Portugal. From 1733 until 1737 they were kept more or less under house arrest in their apartments, prevented from appearing in public and watched by the spies of Queen Elizabeth. This gave Barbara the time to deepen her relationship with Ferdinand, a timid person who suffered also from ill health.
Barbara was not considered beautiful by her contemporaries, and her homely looks were thought by observers to have caused her future husband a visible shock when he was first presented to her. However, 'Ferdinand the Learned' (as he was later known) became deeply attached to her, sharing her passion for music[citation needed] and soon becoming dependent on her for advice and support. When he ascended the Spanish throne as Ferdinand VI, the French ambassador noted "it is rather Barbara who succeeds Elizabeth [Ferdinand's step-mother] than Ferdinand succeeding Philippe." Barbara was well-educated, and in addition to her musical talents was adept at languages and was an avid reader on many varied subjects.
Upon their succession, Barbara was exposed to attempts to drive a political wedge between her and Ferdinand. During her husband's reign, Barbara was to preside over magnificent parties and concerts at her favorite retreat, the Royal Palace of Aranjuez. However, in contrast to her predecessor as queen, Barbara did not like to flaunt her influence over her spouse and the government policy, and she made a moderately positive impression upon the public. She was not as self-assured, nor did she have as much political ambition as Elisabeth Farnese, and her policy focused mainly upon a friendly relationship between Spain and Portugal in cooperation with her father and the Portuguese ambassador Belmonte. Queen Barbara participated regularly in the affairs of state: the ministers, who respected her, presented to her all documents of state before they were given to the king, because: "only she knows what ought either be said or hidden from the king": she was the channel through which the ministers worked with the king, as it was she who advised them how to achieve the desired result from the king, and the ministers relied upon her for their work as, the British ambassador Benjamin Keene reported: "She can sway him as she pleases, with as much power, but much less difficulty, than ever the Dowager did with the late King, his father."
The couple produced no children who survived, with Barbara having a stillborn son in 1733. Barbara suffered from severe asthma for most of her life and in later years became overweight. She died at the Royal Palace of Aranjuez, on the outskirts of Madrid on 27 August 1758. Her death broke her husband's heart. Between the date of her death in August 1758 and his own on 10 August 1759, he fell into a state of prostration in which he would not even dress, but wandered unshaven, unwashed and in a nightgown about his park. The memoirs of the count of Fernán Núñez give a shocking picture of his deathbed.
As the couple had no children, Ferdinand VI of Spain was succeeded as King by his half-brother Charles III.