The insufficient surface properties of multi-principal element alloys (MPEAs) hinder their potential biomedical applications. Here, a facile thermal oxidation plus nitridation treatment is conducted to fabricate a protective layer on a novel Ti-Zr-Nb-Ta-Mo MPEA. The total surface layer of NT5-ON consists of a top compound layer, including TiO2, TiN, TiON, ZrO2, and ZrN, and an underneath N-diffusion zone, leading to an exceptionally high wear performance. Also, electrochemical testing and in-vitro evaluations demonstrated enhanced corrosion resistance and cytocompatibility of NT5-ON. As a result, thermal oxidation plus nitridation treatment is an effective technique for designing high-performance hip implant materials.