Ti–6Al–4V alloy has been widely used as implant materials for biomedical applications. However, the inadequate corrosion resistance and the released metal ions could result in inflammation, cytotoxicity, and shorten the lifespan of implants. To extend the service life of biomaterials, the Ti35Nb25Zr15Mo15V10 high-entropy alloy was designed based on empirical and thermodynamic calculations to achieve a high-performance biomaterial with a potential to replace Ti–6Al–4V alloy. Investigations on the fabricated alloy revealed formation of body-centered cubic solid solution with no intermetallic compound. Nanoindentation experiments indicated a Young's modulus of 118 for the designed alloy which is lower than the elastic modulus of the Ti–6Al–4V alloy. Corrosion behavior of the Ti35Nb25Zr15Mo15V10 and Ti–6Al–4V alloys were investigated and the results represented a low passive current density of ∼10−2 A/m2 for the novel alloy which displayed superior corrosion resistance. In addition, the developed alloy provided higher bio-corrosion resistance compared with the Ti–6Al–4V alloy with superior pitting resistance and low concentration of released ions in a PBS solution. The Ti35Nb25Zr15Mo15V10 alloy revealed acceptable in-vitro biocompatibility performance for adhesion, viability, and proliferation of MG63 pre-osteoblasts. The preliminary benefits of the designed alloy over current metallic implants provide an opportunity to explore the development of new orthopedic-implant alloys.