Abstract: Nanoparticles (NPs) have gained significant attention as a functional material due to their ability to effectively enhance pressure reduction in injection processes in ultra-low permeability reservoirs. NPs are typically studied in controlled laboratory conditions, and their behavior in real-world, complex environments such as ultra-low permeability reservoirs, is not well understood due to the limited scope of their applications. This study investigates the efficacy and underlying mechanisms of NPs in decreasing injection pressure under various injection conditions (25–85 °C, 10–25 MPa). The results reveal that under optimal injection conditions, NPs effectively reduce injection pressure by a maximum of 22.77% in core experiment. The pressure reduction rate is found to be positively correlated with oil saturation and permeability, and negatively correlated with temperature and salinity. Furthermore, particle image velocimetry (PIV) experiments (25 °C, atmospheric pressure) indicate that the pressure reduction is achieved by NPs through the reduction of wall shear resistance and wettability change. This work has important implications for the design of water injection strategies in ultra-low permeability reservoirs.