Background: Several clinically used COX-1 and COX-2 inhibitor drugs were reported to possess severe side effects like GI ulcers and cardiovascular disturbances, respec-tively. Natural products being structurally diverse always attracted the attention of chem-ists/medicinal chemists as a potential source of lead molecules in the drug discovery process. COX-2 inhibitory natural products also possess potential cancer chemopreventive property against various cancers including that of colon, breast and prostate. Methods: Various in vitro, in vivo and in silico standardized methods were used to evaluate COX inhibition property of different secondary metabolites isolated from plant, microbial and marine origin. Results: We had earlier reported a detailed account of natural product inhibitors of COX reported during 1995-2005, in 2006. In the proposed review, we report 158 natural product in-hibitors of COX during 2006 to 2019 belonging to various secondary metabolite classes such as alkaloids, terpenoids, polyphenols as flavonoids, chromones, coumarins, lignans, an-thraquinones, naphthalenes, curcuminoids, diarylheptanoids and miscellaneous compounds of plant and marine origin. Further Structure Activity Relationship (SAR) studies of possible leads are also included in the article. Conclusion: COX inhibitors served as a potential source of lead molecules for the discovery and development of anti-inflammatory drugs. Compilation of natural product and semi-synthetic inhibitors of COX may serve as valuable information to the researchers who are looking for possible lead molecules from a natural source to conduct further preclinical and clinical studies. © 2021 Bentham Science Publishers.