Czech Academy of Sciences in its work continues the research traditions and mission not only of the former Czechoslovak Academy of Sciences but also of its predecessors. The oldest long-lasting learned society was the Royal Czech Society of Sciences (1784-1952) which encompassed both the humanities and the natural sciences. Among its founders were filologist Josef Dobrovský, historian Gelasius Dobner and mathematician and the founder of Prague University Observatory, Joseph Stepling; later it was headed by historian František Palacký.

As early as 1861-1863 Jan Evangelista Purkyně proposed in his treatise Academia the establishment of an autonomous non-university scientific institution associating research institutes representing the main fields of the science of that time. This idea of an institution engaged in interdisciplinary research corresponds to the concept and structure of the present Academy of Sciences.

By the end of the 19th century, language-differentiated scientific institutions arose in this country: the Czech Academy of Science and the Arts (1890-1952, founding charter) and the Association for the Fostering of German Science, Arts and Literature in Bohemia (1891-1945) were established nearly simultaneously. The Czech Academy of Science and the Arts was founded owing to the significant financial support from the Czech architect and builder, Josef Hlávka who became its first President. The aim of this institution was to promote the development of Czech science and literature and to support Czech arts. The most important work of this Academy was its publication activities. Scholarships and financial support were also provided and smaller research units arose upon its initiative as well.

After the foundation of the independent Czechoslovak Republic in 1918 other scientific institutions were established, such as the Masaryk Academy of Labour and autonomous state institutes, such as the Slavonic, Oriental and Archaelogical Institutes. Robust international relationships of Czech research institutions culminated in their affiliation with the International Union of Academies and the International Research Council.

After the totalitarian regime came to power in Czechoslovakia in 1948, all hitherto main scientific non-university institutions and learned societies were dissolved and instead the Czechoslovak Academy of Sciences was founded (1953-1992) comprising both a complex of research institutes and a learned society. Despite having been subjected to heavy ideological pressure until the fall of this regime in 1989, Czech science was nevertheless able to maintain its creative energy in a number of instances and to find its way to the world scientific community (although there were disparities with the various fields of sciences at different periods of the regime). This fact was made evident, among others, by the awarding of the Noble Prize to Jaroslav Heyrovský in 1959 and by the wordlwide recognition attained by Otto Wichterle for his discovery of contact lenses. Otto Wichterle became the first President of the Academy after the revival of democracy in this country. Among other outstanding representatives of Czech science who worked at the Academy in the past, worthy of singular mention are mathematician Eduard Čech, theoretical physicist Václav Votruba, geophysicist Vít Kárník, physiologist Vilém Laufberger and philosopher and co-author of Charter 77 Jan Patočka, to name at least a few.