Maria Sophia was born on August 6, 1666, at the Schloss Benrath in the Holy Roman Empire (now Germany). Her father, Philip William, was the reigning Count Palatine of Neuburg. In 1685, he became the Elector Palatine, which elevated the family's status in Europe. Maria Sophia's sister, Eleonore Magdalene, married Holy Roman Emperor Leopold I, further cementing the family's reputation for producing influential and fertile women.

In Portugal, a succession crisis was unfolding. Isabel Luísa, the heiress to the throne and daughter of King Peter II, had been refused by many European sovereigns due to her frail health and strict Portuguese succession rules. To address this issue, the Portuguese ambassador Manuel da Silva Teles was sent to Heidelberg to propose a marriage alliance with Maria Sophia, with the encouragement of Empress Eleonore Magdalene.

After negotiations, Maria Sophia's marriage to King Peter II was arranged, and the couple had a proxy marriage on July 2, 1687, in Heidelberg. Maria Sophia then embarked on a journey to Portugal, accompanied by an English fleet provided by James II of England. She arrived in Lisbon on August 12, 1687, to great celebrations. The couple had a formal marriage ceremony the same day at the Ribeira Palace.

Maria Sophia quickly won the affection of her stepdaughter, Isabel Luísa, and her husband, King Peter II. She gave birth to a son the following year, but sadly, the child passed away after only three weeks. However, Maria Sophia later gave birth to another son, John, who would succeed his father as John V of Portugal. John V would go on to marry his first cousin, Maria Anna of Austria, daughter of Empress Eleonore Magdalene.

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As queen, Maria Sophia was known for her gentle nature and earned the respect of her husband. She was popular among the people of Portugal and was praised for her generosity. She was actively involved in charitable work, particularly in supporting widows, orphans, and providing medical care to the poor. Her piety also endeared her to the people, and she maintained a close friendship with Father Bartolomeu do Quental, who was revered as a saint. Additionally, Maria Sophia financed the establishment of a Franciscan school in Beja.

Tragically, Maria Sophia's life was cut short when she succumbed to fever, possibly erysipelas, on August 4, 1699, just two days before her thirty-third birthday. She was laid to rest at the Monastery of São Vicente de Fora in Lisbon.

Maria Sophia Elisabeth of Neuburg left a lasting impact on Portugal as a compassionate and devoted queen. Her generosity, piety, and dedication to charitable causes endeared her to the people. Though her reign was relatively brief, she played a significant role in Portuguese history and is remembered as a beloved queen who made a positive difference in the lives of many.