Electrocatalytic nanoparticles that mimic the three-dimensional geometric architecture of enzymes where the reaction occurs down a substrate channel isolated from bulk solution, referred to herein as nanozymes, were used to explore the impact of nano-confinement on electrocatalytic reactions. Surfactant covered Pt-Ni nanozyme nanoparticles, with Ni etched from the nanoparticles, possess a nanoscale channel in which the active sites for electrocatalysis of oxygen reduction are located. Different particle compositions and etching parameters allowed synthesis of nanoparticles with different average substrate channel diameters that have varying amounts of nano-confinement. The results showed that in the kinetically limited regime at low overpotentials, the smaller the substrate channels the higher the specific activity of the electrocatalyst. This is attributed to higher concentrations of protons, relative to bulk solution, required to balance the potential inside the nano-confined channel. However, at higher overpotentials where limitation by mass transport of oxygen becomes important, the nanozymes with larger substrate channels showed higher electrocatalytic activity. A reaction-diffusion model revealed that the higher electrocatalytic activity at low overpotentials with smaller substrate channels can be explained by the higher concentration of protons. The model suggests that the dominant mode of mass transport to achieve these high concentrations is by migration, exemplifying how nano-confinement can be used to enhance reaction rates. Experimental and theoretical data show that under mass transport limiting potentials, the nano-confinement has no effect and the reaction only occurs at the entrance of the substrate channel at the nanoparticle surface.