Over the last decade, researchers have paid more and more attention to the natural compound curcumin for its potential application in anticancer therapy. However, the application of curcumin has been limited owing to its rapid metabolism in the body. HO-3867, a stable curcumin analog, shows potent antitumor activities against various tumor cells. Yet, information on HO-3867’s impact on non-small-cell lung cancer (NSCLC) cells is lacking. Herein, we evaluated the cytotoxicity of HO-3867 in NSCLC cells. We discovered that HO-3867 suppressed the viability of NSCLC cells containing wild-type p53. In NSCLC cells, HO-3867 promotes both apoptosis and ferroptosis, the latter of which is a newly discovered mode of cell death. Mechanically, HO-3867-induced apoptosis relied on the inhibition of Mcl-1 and Bcl-2 and the upregulation of Bax. Moreover, NSCLC cells undergo ferroptosis when treated with HO-3867 via activating the p53-DMT1 axis and suppressing GPX4. Additionally, HO-3867 caused an accumulation of reactive oxygen species (ROS) in NSCLC in a way that was dependent on the presence of iron. Our findings point to the possibility that HO-3867 might be employed as a therapeutic agent for treating NSCLC.