In this work, thermo-mechanically treated 42CrMo steel was subjected to cryogenic treatment conducted by means of orthogonal design method, followed by low-temperature tempering to investigate the effect of different parameters of cryogenic treatment on wear resistance of 42CrMo steel and to optimize parameters of cryogenic treatment for improving wear resistance. The results of hardness test and wear test show that cryogenic treatment significantly improves wear resistance with marginal changes in coefficient of friction and hardness. Specifically, cryogenic temperature has the largest impact on wear resistance of 42CrMo steel, holding time has medium impact, and the parameter of treatment cycles has the least impact. The optimum parameters of cryogenic treatment are −196°C for 12 hours with one cycle for improving wear resistance. The results of scanning electron microscopy (SEM) and X-ray diffractometry (XRD) analysis indicate that marginal changes in hardness and coefficient of friction may be owing to little amount of transformation of retained austenite, and the significant influence of cryogenic treatment on improving wear resistance of 42CrMo steel can be mainly attributed to segregation of carbon atoms promoted by cryogenic treatment resulting in more precipitation of carbides in subsequent tempering.