She was born at the Royal Alcázar of Seville in Seville and was the youngest daughter of Philip V of Spain and of his second wife Elisabeth Farnese. She was born in Seville during the signing of the Treaty of Seville which ended the Anglo-Spanish War. She spent her infancy in the city of her birth before moving to Madrid in 1733. She was baptised with the names María Antonia along with Fernanda in honour of her half brother, then the heir to the throne. Variations in her name range from "Antonia Fernanda" and "Antonietta Ferdinanda". As a daughter of the King of Spain, she held the title of Infanta of Spain and style of Royal Highness. In a double marriage plan she would marry Louis, Dauphin of France, and her brother, Infante Philip, would marry the Dauphin's sister Louise Élisabeth of France. Her mother consented to the latter union but insisted on waiting for Maria Antonia Ferdinanda to reach a more mature age. The Infanta's hand was also sought by the Electoral Prince of Saxony. The marriage between Infante Philip and Louise Élisabeth occurred in 1739 and eventually her older sister Infanta Maria Teresa Rafaela married the Dauphin in 1745. However, upon the death of Maria Teresa Rafaela in 1746 Ferdinand VI tried to engage Maria Antonia Fernandina to the Dauphin but the idea was snubbed by Louis XV as "incest". Instead he chose Maria Josepha of Saxony.
Having married by proxy in Madrid on 12 April 1750 she was married in person at Oulx on 31 May 1750 to Victor Amadeus, Duke of Savoy, the eldest son of Charles Emmanuel III of Sardinia and his late wife Polyxena of Hesse-Rotenburg. The marriage had been arranged by Maria Antonia Ferdinanda's half brother, Ferdinand VI and was used to strengthen relations between Madrid and Turin as the two courts had fought on opposing sides during the War of the Austrian Succession. The Treaty of Aix-la-Chapelle ended the war. As a wedding gift, the apartments of the new Duchess of Savoy at the Royal Palace of Turin were remodelled by the architect Benedetto Alfieri. Maria Antonia Ferdinanda was given a dowry of 3,500,000 Piedmontese Lires as well as Spanish possessions in Milan. In Italy she was known as Maria Antonietta Ferdinanda. Operas by Baldassare Galuppi were specially composed for her marriage to the Duke of Savoy. The match was seen as unpopular, but the two remained close until her death. From marriage until her husband's accession she was styled as the Duchess of Savoy. The couple surrounded themselves with modern thinkers and various politicians. The first lady of the land, she brought a rigid etiquette from her native Spain to the court of Savoy. She was very religious and was said to have a cold, shy personality. She was the mother of twelve children, three of whom died in infancy. Two of her children had issue. Through her son Victor Emmanuel I and daughter Maria Teresa of Savoy, she is a double ancestress of Queen Anne of Romania as well as the pretending Duke of Parma, Emperor of Austria and reigning Grand Duke of Luxembourg.