[1][2] The marriage of her parents was purely made for political reasons, mainly the search for a new male heir for the Spanish throne after the early death of Balthasar Charles, Prince of Asturias in 1646.

Besides him, the other only surviving child of Philip IV's first marriage was the Infanta Maria Theresa, who later became the wife of King Louis XIV of France.

After Margaret, between 1655 and 1661, four more children (a daughter and three sons) were born from the marriage between Philip IV and Mariana of Austria, but only one survived infancy, the future King Charles II of Spain.

[7][8] In the second half of the 1650s at the imperial court in Vienna the necessity developed for another dynastic marriage between the Spanish and Austrian branches of the House of Habsburg.

At first the proposals were for Maria Theresa, the eldest daughter of Philip IV, to marry the heir of the Holy Roman Empire, Archduke Leopold Ignaz.

[11] In October 1662, the new Imperial ambassador in Spain, Count Francis Eusebius of Pötting, began one of his main diplomatic assignments, which was the celebration of the marriage between the infanta and the emperor.

In his will, he did not mention Margaret's betrothal; in fact, the context in which the document was prepared suggests that the late monarch still hesitated to marry his daughter to his Austrian relative because he sought to ensure her rights as sole ruler of the Spanish crown in case of the extinction of his male line.

[14] Mariana of Austria, now Dowager Queen and Regent of the kingdom on behalf of her minor son Charles II, delayed the wedding of her daughter.

On 25 April 1666, the marriage by proxy was finally celebrated in Madrid, in a ceremony attended not only by the Dowager Queen, King Charles II and the Imperial ambassador but also by the local nobility; the groom was represented by Antonio de la Cerda, 7th Duke of Medinaceli.

The infanta arrived at Dénia, where she rested for some days before embarking on the Spanish royal fleet on 16 July, in turn escorted by ships of the Order of Malta and the Grand Duchy of Tuscany.

Then (after a short stop in Barcelona because Margaret had some health issues)[16] the cortege sailed to the port of Finale Ligure, arriving on 20 August.

On 8 October the Spanish retinue arrived at the city of Roveredo, where the head of Margaret's cortege, Francisco Fernández de la Cueva, 8th Duke of Alburquerque officially handed the infanta to Ferdinand Joseph, Prince of Dietrichstein and Count Ernst Adalbert von Harrach, Prince-Bishop of Trent, representants of Leopold I.

On 20 October the new Austrian cortege left Roveredo, crossing the Tyrol, through Carinthia and Styria, and arrived on 25 November at the district of Schottwien, twelve miles from Vienna where the emperor came to receive his bride.

Surrounded almost exclusively by her native retinue (which included secretaries, confessors, and doctors), she loved Spanish music and ballets and therefore hardly learned the German language.

Only four months later, the widower emperor – despite his grief for the death of his "only Margareta" (as he remembered her)[24] – entered into a second marriage with Archduchess Claudia Felicitas of Austria, member of the Tyrolese branch of the House of Habsburg.

[30][31] The Infanta Margarita Teresa in a Pink Dress (1660), formerly credited to Velázquez, is now considered one of the masterpieces of his son-in-law, Juan Bautista Martínez del Mazo.