The Strakonice museum was established in 1894. The establishment was inspired by the Czechoslavic Ethnographic Exhibition organized in Prague in 1895. Since 1923 the museum had been named after Jan Dyk, the district School Inspector, who played a key role in its development and re-opening after the war. It had moved several times before it was finally seated in the castle premises in 1936 and the expositions were opened for public in May 1937 on the occasion of the visit of the Czechoslovakian President Edvard Beneš in Strakonice.
The Second World War affected the museum adversely and its activities were completely suspended. By decision of the Regional People's Committee in České Budějovice from March 1951 the original town museum became a district museum and in 1953 it was renamed to the District Museum of National History and Geography in Strakonice. Its statutory authority was the District People's Committee of Strakonice (District Authority, from December 1989 to 31st December 2002).
An important milestone was the year of 1955 when the separation of the museum and archive took place, namely on 1st January. In 1967 the museum received its current name – Museum of Central Otava Region. Along with the public administration reform the museum became a regional museum as of 1st January 2003, the statutory authority of which is the South Bohemian Region.