Simonida was born in Constantinople ca. 1294. In 1298, as a result of a Byzantine defeat, Emperor Andronikos II promised a marriage alliance to the Serbian ruler Milutin. Initially, Andronikos II intended to wed his sister Eudokia, the empress-dowager of Trebizond, but after she refused, Simonida was proposed instead. Church circles in Constantinople opposed the marriage, but the emperor was determined to push the deal through, and in late 1298 he sent his trusted minister Theodore Metochites to Serbia to conduct the negotiations. On his part, Milutin too was eager to accept, and even divorced his third wife, Ana Terter, the daughter of the Bulgarian tsar George Terter. Simonida was five years old, and Milutin was almost 50, was married three times, with adult children. The marriage was celebrated in Thessalonica in spring 1299, and the couple departed for Serbia in April. As a wedding present, Byzantines recognized Serbian rule north of the line Ohrid—Prilep—Štip.
According to some Byzantine sources Milutin did not wait until Simonida reached maturity before consummating their relationship, causing damage to her uterus and preventing her from ever carrying children. When this became known, Empress Irene, who was Andronikos II's second wife and had hoped to use the Serbian marriage to advance her own progeny, then offered Milutin to adopt one of her own sons as his heir.
Simonida showed great interest in theology and wanted to become a nun. After her mother Irene died in 1317, Simonida attended her funeral in Constantinople and decided not to return to Serbia. When Milutin's men came for her, she came to them in monastic habit. They were shocked, but her own half-brother Constantine Palaiologos took off her monastic habit and ordered her to take civil dress. He then sent her to Serbia with Milutin's men, although she was reluctant to go. After Milutin threatened to start a war, Simonida came back to him. She was 22 years old. When Milutin fell ill, she was beside him all the time, much to the surprise of the rest of the court. Milutin died on 19 October 1321, and already on 29 October, Simonida returned to Constantinople, where she entered the monastery of Saint Andrew in Krisei as a nun.
There is very little information about her later life. It is known that she order a
funeral song for her father's funeral. Simonida was last mentioned in historic documents in 1336 as an attendee at an assembly of civil and religious dignitaries, who prosecuted the conspirators against the government. She died some time after 1345.