In this study, we synthesized thirteen derivatives by performing Steglich esterification on one or both phenolic rings of curcumin, aiming to enhance their anti-inflammatory activity. The monofunctionalized compounds exhibited superior bioactivity compared to the difunctionalized ones, particularly in terms of inhibiting IL-6 production. Among all the derivatives, compound 2 showed the highest activity in this regard. Additionally, compound 2 demonstrated strong activity against PGE2 synthesis. Through structure-activity relationship studies, we found that the presence of a free hydroxyl group or aromatic ligands on the curcumin ring, along with the absence of a linker moiety, contributed to increased activity. Compound 2 remained the most effective in modulating IL-6 production and showed potent activity against PGE2 synthesis.