The CCDC grew out of the activities of the crystallography group led by Dr Olga Kennard OBE FRS in the Department of Organic, Inorganic and Theoretical Chemistry of the University of Cambridge. From 1965, the group began to collect published bibliographic, chemical and crystal structure data for all small molecules studied by X-ray or neutron diffraction. With the rapid developments in computing taking place at this time, this collection was encoded in electronic form and became known as the Cambridge Structural Database (CSD).

The CSD was one of the first numerical scientific databases to begin operations anywhere in the world, and received academic grants from the UK Office for Scientific and Technical Information and then from the UK Science and Engineering Research Council. These funds, together with subventions from National Affiliated Centres, enabled the development of the CSD and its associated software during the 1970s and 1980s. The first releases of the CSD System to the USA, Italy and Japan occurred in the early 1970s. By the early 1980s the CSD System was being distributed in more than 30 countries worldwide. The CSD System is now distributed to academics in 70 countries worldwide.

During the 1980s, interest in the CSD System from pharmaceutical and agrochemicals companies increased significantly. This additional income stream enabled the CCDC to become an independent company in 1987, with the legal status of a non-profit charitable institution, and with its operations overseen by an international Board of Governors. The CCDC moved into purpose-built premises on the site of the University Department of Chemistry in 1992.

Dr Kennard retired as Director in 1997 and was succeeded by Dr David Hartley (1997-2002), Dr Frank Allen (2002-2008) and Dr Colin Groom (2008-2017). Dr Jürgen Harter was appointed as Chief Executive Officer from 10 July 2018.

CCDC software products have now diversified to make maximum use of crystallographic data in applications in the life sciences and crystallography.

Although CCDC is now a self-administering organisation, it retains close links with the University of Cambridge, and is a University Partner Institution that is qualified to train postgraduate students for higher degrees (PhD, MPhil).

The CCDC established US applications and support operations in the USA in October 2013.