NF-κB is a critical target for cancer treatment due to its central role in facilitating cancer progression and desensitizing cancer cells to chemotherapeutic drugs. In this study, a series of chemically modified asymmetric curcuminoid analogs named S01-S15 were synthesized and evaluated for NF-κB inhibitory activity in gastric cancer cell lines. Cell growth inhibition assays revealed that most of these analogs effectively inhibited the growth of BGC-823, SGC-7901, and MFC cells. S06 was selected for further research. MTT assay, clonogenic assay, Hoechst 33258 staining assay, and western blotting revealed that S06 could exert anti-gastric cancer effects by downregulating NF-κB activity. Moreover, via its effects on NF-κB, S06 effectively enhanced the sensitivity of the gastric cancer cells to irinotecan. Together, this study provide a series of new curcuminoid analogs as promising cancer therapeutic agents.