Running-in is essential for improving the performance and lifetime of a machine. This study proposed a two-stage running-in procedure based on the lubrication regime and nanoparticle effect to increase running-in efficiency; the method was verified using a disk-on-block experiment. The first stage involved wearing down the high peaks of the surface asperities in relatively severe mixed lubrication. The second stage was a mild wear process, in which the shape of the asperity peak was trimmed with soft CuO particles in three-body mixed lubrication. The CuO concentrations were divided into three concentration variations (0.1 wt%, 0.5 wt%, and 1.0 wt%) to investigate the effect of CuO concentration on the smoothing surface processes. The tribological parameters, including the surface roughness value, peak radius of asperity, plasticity index, adhesion index, real contact area, true friction power intensity (TFPI), and modified true friction power intensity (MTFPI) index, were investigated to evaluate the friction coefficient, wear, and anti-scuffing performance. The result after first stage showed that the surface roughness value decreased to similarly low values for the different initial roughness values. After the second stage of the trimming process, the asperity peak radius, contact angle, real contact area, plasticity index, and anti-scuffing improved considerably. The obvious reduction in the friction coefficient in the second stage was due to the decrease in ratchet friction, deformation, and plowing friction. These methods effectively enhanced the efficiency of the running-in process.