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.

[2] 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.

[3] 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.

[4] 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.

[3] After her mother Irene died in 1317, Simonida attended her funeral in Constantinople and decided not to return to Serbia after nearly a decade and a half of discussion.

Simonida was last mentioned in historical documents in 1336 as an attendee at an assembly of civil and religious dignitaries, who prosecuted the conspirators against the government.