The hypoxic environment within a solid tumor is a limitation to the effectiveness of photodynamic therapy. Here, we demonstrate the use of oxygen generating nanozymes (CeO 2 , Fe 3 O 4 , and MnO 2 ) to improve the photodynamic effect. The optimized combination of process parameters for irradiation was obtained using the Box Behnken experimental design. Indocyanine green, IR 820, and their different combinations with oxygen generators were studied for their effect on oral carcinoma. Dynamic light scattering technique showed the average particle size of CeO 2 , MnO 2 , and Fe 3 O 4 to be 211 ± 16, and 157 ± 28, 143 ± 19 nm with PDI of 0.23, 0.28 and 0.20 and a zeta potential of -2.6 ± 0.45, -2.4 ± 0.60 and -6.1 ± 0.23 mV, respectively. The formation of metal oxides was confirmed using UV-visible, FTIR, and X-ray photon spectroscopies. The amount of dissolved oxygen produced by CeO 2 , MnO 2 , and Fe 3 O 4 in the presence of H 2 O 2 within 2 min was 1.7 ± 0.15, 1.7 ± 0.16, and 1.4 ± 0.12 mg/l, respectively. Growth inhibition studies in the FaDu oral carcinoma spheroid model showed a significant (P < 0.05) increase in growth reduction from 81 ± 2.9 and 88 ± 2.1% to 97 ± 1.2 and 99 ± 1.0% for ICG and IR 820, respectively, after irradiation (808 nm laser, 1 W/cm 2 , 5 min) in the presence of CeO 2 (25 μg/ml). In conclusion, oxygen-generating nanozymes can improve the photodynamic effect of ICG and IR 820.