Interfacial tension (IFT) is an interfacial phenomenon that commonly exist between immiscible liquids such as oil and brine that are found in the hydrocarbon reservoirs. High IFT in combination with high capillary forces plays a fundamental role in residual oil saturation in the reservoir rock pores. The effects of enzyme and silica nanoparticles on crude oil-water and crude oil-brine interactions were investigated and presented in this study. The potential of individual application of enzyme and silica nanoparticles as well as the combination of both were explored under different salinity conditions. The results of this study showed that the application of silica nanoparticles did not significantly reduce oil-brine IFT under different salinity conditions investigated in this study, although the highest reduction was obtained with low salinity brine. The use of enzyme however significantly reduced oil-brine IFT under varied salinity conditions and better IFT reduction was obtained in brines relative to aqueous solution. Finally, the combination of enzyme with nanoparticles effected better IFT reduction than the application of either of them individually in aqueous solution and it also significantly reduced oil-brine IFT in all salinity conditions. This study is a novel investigation on the potential of enzyme-nanoparticles to modify oil-brine IFT and the result of this study is significant to the design and application of enzyme and nanoparticles enhanced oil recovery processes.