The current work considers mono, mixed SiO2, and CuO nanofluid application in very-high mass-flux spray cooling. At first, the modified sol-gel method based SiO2 and wet-chemical method based CuO nanoparticles are prepared. After that, nanoparticles are characterized for density, surface area, crystalline/amorphous nature, functional groups, compositions, morphology, and particle size. The SiO2 and CuO nanofluid are prepared using one-step and two-step methods, respectively. The nanofluid is characterized for thermophysical properties, particle size distribution, and stability. The applied mono or mixed nanofluid performance is assessed in terms of cooling rate, heat flux, and heat transfer coefficient, estimated using inverse heat conduction analysis. An improvement in cooling rate is observed with concentration enhancement for all nanofluids, owing to thermal conductivity and nucleation site enhancement. However, for mono CuO and mixed SiO2-CuO nanofluid at their highest concentration, the cooling enhancement rate decreases as compared to water, which may be attributed to nucleation sites blockage by high-density CuO excessive deposition. The highest 162 oC/s cooling rate is observed at the highest mixed nanofluid concentration. The average surface heat flux, critical heat flux, and average heat transfer coefficient improvement are maximum at1.68 MW/m2, 2.64 MW/m2, 2.56 kW/m2K, respectively, for mixed nanofluid at their highest concentration.