The town's first written mention dates to 1455. The construction of Biržai Castle began in 1586, and the town was granted Magdeburg Rights in 1589. In 1575, as preparation for the castle's construction, a dam was built on the Agluona and Apaščia Rivers at their confluence, and the artificial Lake Širvėna, covering about , was created. It is the oldest surviving artificial lake in Lithuania. The town's history is closely associated with the Radziwiłł family (Lithuanian: Radvila). Jerzy Radziwiłł was the first noble to settle in the town. Later, after his daughter, Barbara Radziwiłł married the Grand Duke of Lithuania and King of Poland Sigismund II Augustus in 1547, the power and influence of the family grew immensely. The Radvila family established a Protestant church and school, and the town became a cultural center of the Protestant Reformation in Lithuania.