Abstract Background/purpose Curcumin is a polyphenolic phytochemical isolated from the medicinal plant Curcuma longa L. This phytochemical exhibits anti-inflammatory and antioxidant properties. The aim of this study was to find a curcuminoid compound that has a better effect on the suppression of interleukin-1β (IL-1β)-induced IL-6 production than curcumin in human gingival fibroblasts (HGFs). Materials and methods The parent curcuminoids 1–3 were isolated from the rhizomes of C. longa and 17 curcuminoid analogs 4–20 were synthesized from the parent curcuminoids. The condition for IL-6 production by HGFs after inducing the cells with IL-1β was optimized. HGFs were incubated with curcuminoids (0.016–20 μg/mL) for 30 minutes before adding IL-1β (2 ng/mL). After 24 hours of incubation, the culture media were harvested and determined for IL-6 contents using an enzyme-linked immunosorbent assay method. Prednisolone, an immunosuppressive drug, was used as a positive control. Half maximal effective concentration (EC50) is measured and reported as the concentration required for 50% inhibition of the levels found in the control medium. Results The maximum IL-6 production was achieved when the HGFs were exposed to an IL-1β concentration of 2 ng/mL for 24 hours; however, addition of the immunosuppressant prednisolone inhibited the production of IL-6. Among the analogs, di-O-demethylcurcumin (5) exhibited the most potent anti-IL-6 activity with an EC50 of 2.18 ± 0.07 μg/mL, which was approximately eightfold more active than the natural curcuminoids 1–3. Cell viability was not significantly affected when the concentration of di-O-demethylcurcumin was less than 20 μg/mL. Conclusion Di-O-demethylcurcumin exhibited an inhibitory effect on the production of IL-6 by IL-1β-induced HGFs and can thus serve as a lead compound with its inhibiting property for IL-6 production.