<p>Curcumin, predominantly derived from <i>Curcuma longa</i>, is widely recognized for its anti-inflammatory properties. However, its clinical application is hindered by challenges such as poor stability and low bioavailability. To address these issues, extensive research has focused on modifying the structure of curcumin in order to enhance its stability and efficacy. Among the structurally-modified curcumin analogues, 4-piperidone-based curcumin analogues have emerged as promising candidates with significant anti-inflammatory potential. This review discusses about anti-inflammatory effects and the underlying mechanisms of these structurally modified 4-piperidone-based curcumin analogues, as well as their activities on several inflammation-related signaling pathways and pro-inflammatory mediators. Moreover, we also review about the structure–activity relationships of these analogues, providing new insights for the development of novel 4-piperidone-based curcuminoids. Piperidone-based curcumin analogues generally show significantly stronger anti-inflammatory effects compared to their linear 5-carbon linker counterparts. Notably, analogues containing <i>N</i>-methyl-4-piperidone linkers have demonstrated superior efficacy. The properties of substituents on both sides of aromatic side chain plays a significant role in modulating their anti-inflammatory activity. Beneficial groups such as methoxy groups, and electron-withdrawing substituents have been shown to enhance the anti-inflammatory effect by suppressing pro-inflammatory enzymes and cytokines via the regulation of key pathways, including LOX, COX, NF-κB and MAPK. Overall, these novel curcumin analogues hold significant potential as effective anti-inflammatory agents.</p> Graphical abstract <p></p>