The imposing palace made of local red sandstone is one of the most important residences from the German Late Renaissance period. It was built from 1605 for the Mainz elector and archbishop Johann Schweikard von Kronberg (r. 1604–1626) by the Strasbourg architect Georg Ridinger (1568–1616), and took only nine years to complete. The palace was inaugurated on 17 February 1614 and the electoral archbishop moved in a year later.
Johannisburg Palace was built on the site of a medieval castle, most of which had been destroyed in 1552. Ridinger created a perfectly symmetrical four-winged complex with a square inner courtyard and four corner towers, and incorporated the 13th-century keep in the new building. The windows, gates and doors of the exterior and interior courtyard façades are decorated with architectural ornamentation which is particular elaborate in the triangular gables. The portal of the palace chapel features sculptures by Hans Juncker.
At the end of the 18th century the Aschaffenburg palace was modernized under Friedrich Karl Joseph von Erthal (r. 1774–1802). The arcades in the courtyard were demolished, a third entrance was added to the town wing and a balcony was built over the main portal. Changes were also made to the interior of the palace, which was redesigned in the Neoclassical style. The architect responsible was Emanuel Joseph von Herigoyen (1746–1817), who completed further projects for Erthal such as Schönbusch Palace and the buildings in the Schönbusch landscape park.
During the Second World War Johannisburg Palace was badly damaged. It was rebuilt between 1954 and 1964. While the exterior was reconstructed in its original form, the floor plan was changed to enable the building to be used as a museum, administrative offices and a library. Renovation of the palace in several phases has been in progress since 2016 and in 2023 the River Main wing with the Aschaffenburg State Gallery, the Parament Chamber and the Princely Apartments was reopened.