Efficiency and durability are among the top concerns in mechanical design to minimize environmental impact and conserve natural resources while fulfilling performance requirements. Today mechanical systems are more compact, lightweight, and transmit more power than ever before, which imposes great challenges to designers. Under the circumstances, some simplified analyses may no longer be satisfactory, and in-depth studies on mixed lubrication characteristics, taking into account the effects of 3D surface roughness and possible plastic deformation, are certainly needed. In this paper, the recently developed plasto-elastohydrodynamic lubrication (PEHL) model is employed, and numerous cases with both sinusoidal waviness and real machined roughness are analyzed. It is observed that plastic deformation may occur due to localized high pressure peaks caused by the rough surface asperity contacts, even though the external load is still considerably below the critical load determined at the onset of plastic deformation in the corresponding smooth surface contact. It is also found, based on a series of cases analyzed, that the roughness height, wavelength, material hardening property, and operating conditions may all have significant influences on the PEHL performance, subsurface von Mises stress field, residual stresses, and plastic strains. Generally, the presence of plastic deformation may significantly reduce some of the pressure spikes and peak values of subsurface stresses and make the load support more evenly distributed among all the rough surface asperities in contact.