Abstract: Piperlongumine, an alkaloid containing a dihydropyridine moiety and derived from long pepper, has been extensively investigated for its observable therapeutic properties, particularly its anti-inflammatory action. Multiple in-vitro experimental models simulating inflammatory diseases have shown its anti-inflammatory efficacy. Piperlongumine, displayed a strong inhibitory effect on the major inflammatory signaling cascades, including MAPK, NF-κB, and JAK/STAT, which was followed by a gradual decrease in the gene-protein expression of cyclooxygenase-inducible nitric oxide synthase and other inflammatory proteins. Moreover, Piperlongumine, efficiently deteriorates the protein activity of neutrophil elastase by regulating the endogenous ANXA1 gene expression, lowering the inflammation in the lungs and other bodily organs. This review examines the anti-inflammatory mechanism and origin of Piperlongumine, as well as its toxicity and biological resources as a therapeutic molecule with additional pharmacological benefits. In addition, the different chemical variants of Piperlongumine, that have been discovered in recent years, as well as its structural orientation in the context of its anti-inflammatory effect, have been used in this study. © 2023, Pleiades Publishing, Ltd.