The growing number of publications concerning postoperative cognitive decline (POCD) after cardiac surgery is indicative of the health-related and economic-related importance of this intriguing issue. Significantly, the reported POCD incidence over the years has remained steady due to various unresolved challenges regarding the examination of this multidisciplinary topic. In particular, a universally accepted POCD definition has not been established, and the pathogenesis is still vaguely understood. However, numerous recent studies have focused on the role of the inflammatory response to a surgical procedure in POCD occurrence. Therefore, this traditional narrative review summarizes and evaluates the latest findings, with special attention paid to the difficulties of defining POCD as well as the involvement of inflammation in POCD development. We searched the MEDLINE, Scopus, PsycINFO and CENTRAL databases for the best evidence, which was classified according to the Oxford Centre for Evidence-based Medicine. To our knowledge, this is the first narrative review that identified class-1 evidence (systematic review of randomized trials), although most evidence is still at class-2 or below. Furthermore, we revealed that defining POCD is a very controversial matter and that the inflammatory response plays an important role in the mutually overlapping processes included in POCD development. Thus, developing the definition of POCD represents an absolute priority in POCD investigations, and the inflammatory response to cardiac surgery merits further research.