Spray cooling is a heat transfer technology that has already shown its advantages and limitations. There has been increasing interest from academia and industry in combining this technology with nanofluids as coolants, owing to their potential for heat transfer enhancement. Nevertheless, there is a lack of understanding of the physical mechanism leading to this enhancement with the presence of technical problems that prevent the use of nanofluids in spray cooling applications. In this study, we investigate the effect of water-based TiO2 nanofluids on both spray characteristics and heat transfer using an industrial full-cone pneumatic nozzle. For this purpose, three mass concentrations (0.05 wt.%, 0.1 wt.%, and 0.2 wt.%) were prepared and tested. We monitored the droplet sizes and velocity profiles with a particle dynamics analysis system. Moreover, the temporal temperature decrease of a heated aluminum block from 190 to 65 °C was measured via an infrared camera to calculate the heat transfer rate and heat transfer coefficient. The presence of nanoparticles is shown not to substantially alter the spray characteristics. Moreover, heat transfer is augmented mainly in the boiling regime due to more nucleation sites formed by the deposited nanoparticles. However, in the non-boiling regime, the contribution of adsorbed nanoparticles to the heat transfer enhancement diminishes. Overall, the aluminum block is cooled down 6%, 12%, and 25% faster than the DI water by the nanofluids at 0.05 wt.%, 0.1 wt.%, and 0.2 wt.%, respectively, including boiling and non-boiling regimes.