BACKGROUND: Iron oxide nanoparticles coated with paclitaxel (IONP@PTX) are frequently applied to various tumor types. However, inhibitory effect and possible mechanism of IONP@ PTX on non-small-cell lung cancer (NSCLC) remain unclear. OBJECTIVE: This work aimed to assess inhibitory effects and potential mechanisms of IONP@PTX on lung cancer A549 cells and further explore the nanomedicine delivery systems for applications in cancer therapies. METHODS: Morphology features and qualities of IONP@PTX were directly assessed. After treatment of A549 cells with either PTX or IONP@PTX, cell viability and apoptosis were separately detected by CCK‑8 assay and flow cytometry. In addition, intracellular iron ion, lipid peroxidation (LPD) and reactive oxygen species (ROS) were identified by using an iron colorimetric assay kit, DCFH-DA and C11-BODIPY fluorescent probe, respectively. Moreover, the expression levels of autophagy-, ferroptosis-, and apoptosis-related proteins were measured by Western blot. RESULTS: The synthesized IONP@PTX had a core particle size of about 10 nm and a hydrated particle size of 31.01±2.47 nm. In comparison with PTX, IONP@PTX had a stronger anti-tumor effect on A549 cells, with considerably higher levels of ROS, LPD, and total iron ion concentration (P<0.05). Likewise, IONP@PTX markedly reduced the expression levels of GPX4, FTH, and SLC7A11 proteins whereas obviously increased the expression levels of LC3II/I and ACSL4 proteins (P<0.05). Furthermore, the inhibitory effects of both PTX and IONP@PTX on A549 cells could be evidently reversed by additional 3-methyladenine (3-MA) or ferrostatin-1. Interestingly, the apoptosis rates of A549 cells, together with the expression level of pro-apoptotic protein Cleaved caspase-3, were significantly higher in the IONP@PTX group than those in the control and PTX groups (P<0.05). CONCLUSION: IONP@PTX inhibits the proliferation of human lung cancer A549 cells by enhancing autophagy-dependent ferroptosis and apoptosis pathways.