Abstract: Background　Microwave thermal-dynamic therapy is a promising alternative treatment for oral cancer, but currently, research on it is extremely limited.Objective　To investigate the role of ferrocene-doped zirconium-based metal–organic framework nanoparticles (ZrMOF-Fc NPs) in enhancing microwave thermal – dynamic therapy and to elucidate their cytotoxic effects on oral squamous cell carcinoma Cal-27 cells. Methods　Dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and energy-dispersive X-ray spectroscopy (EDS) elemental mapping were used for physicochemical characterization. A near-infrared thermal imaging system was used to monitor temperature changes of ZrMOF-Fc NPs at different concentrations (1, 3, 5 mg/mL) under microwave irradiation. The 3,3′ ,5,5′-tetramethylbenzidine (TMB) colorimetric assay was used to evaluate hydroxyl radical generation with or without microwave irradiation and under microwave irradiation at different concentrations of ZrMOF-Fc NPs (0, 5, 10, 15, 20 μg/mL). Cell Counting Kit-8 (CCK-8) and live/dead cell staining were used to assess the viability of Cal-27 and HOK cells treated with different concentrations of ZrMOF-Fc NPs (0, 25, 50, 100, 200 μg/mL). Cal-27 cells were divided into a control group, a microwave group, and a microwave+ZrMOF-Fc group (25, 50, 100, 200 μg/mL); CCK-8 was used to determine cell viability in each group. Live/dead cell staining was performed at 200 μg/mL for validation, and DCFH-DA fluorescence was used to measure intracellular reactive oxygen species (ROS) levels.Results　ZrMOF-Fc NPs were quasi-spherical with an average diameter of 269.3 ± 0.5 nm. Under microwave irradiation, the solution temperature increased markedly and rose with increasing concentration. Compared with the non-microwave group, microwave irradiation significantly enhanced the TMB reaction, and the enhancement increased with higher material concentrations. In Cal-27 and HOK cells, there was no significant difference in viability between the 25 - 200 μg/mL groups and the 0 μg/mL group (P＞0.05). In the treatment experiment, the 200 μg/mL+microwave group showed the most pronounced decrease in viability (P＜0.001); at 200 μg/mL, the microwave+ZrMOF-Fc group exhibited the highest number of dead cells and the strongest ROS signal. Conclusion　ZrMOF-Fc NPs show good biosafety and efficient microwave thermal-dynamic conversion capability, and can significantly kill Cal-27 cells.