Historical sources indicate that in the 16th century, on the site of the present-day Vilnius Radvila Palace, then called Didžiieji Lukiškės, in a park-like garden behind the city's defensive wall, next to the Villa Gate, stood the palace of Mikolaj Radvila the Black. In the middle of the 17th century, the Grand Hetman of Lithuania and the Governor of Vilnius, Jonušas Radvila (1612-1655), built a residential palace according to a design by the architect Jonas Ulrichs. The palace, with Renaissance forms and a U-shaped plan with Mannerist decoration, consisted of four two-storey blocks connected by five three-storey pavilions in the corners. The inner courtyard was enclosed on the south-west side by a low masonry fence with two gates. This palace is depicted on a medal by the German medallist Sebastian Dadler (1586-1657), struck on the occasion of the inauguration of Jonušas Radvila as Governor of Vilnius in 1653. The palace is depicted in watercolours by Vytautas Gabriūnas (1930-1992).

In the middle of the 17th century, the Radvila Palace was one of the most beautiful in Vilnius. People did not enjoy it for long. Wars and fires in the mid-17th and early 18th centuries devastated them. At the beginning of the 19th century, Dominykas Radvila (1786-1813), the owner of the palace at that time, handed over the abandoned, uninhabited palace to the Vilnius Charitable Society, which managed it until 1940. During the charity's tenure, the dilapidated blocks of the palace were demolished or rebuilt from the ground up.

In 1967, restoration work began in the Radvilas' residence palace. At that time, only 2 wings of the palace (the north and east wings) and one north pavilion remained. In 1984, the second pavilion, the west pavilion, was also restored.