Obtaining a suitable chemical composition for high-entropy alloys (HEAs) with superior mechanical properties and good biocompatibility is still a formidable challenge through conventional trial-and-error methods. Here, based on a large amount of experimental data, a machine learning technique may be used to establish the relationship between the composition and the mechanical properties of the biocompatible HEAs. Subsequently, first-principles calculations are performed to verify the accuracy of the prediction results from the machine learning model. The predicted Young’s modulus and yield strength of HEAs performed very well in the previous experiments. In addition, the effect on the mechanical properties of alloying an element is investigated in the selected Ti-Zr-Hf-Nb-Ta HEA with the high crystal symmetry. Finally, the Ti₈-Zr₂₀-Hf₁₆-Nb₃₅-Ta₂₁ HEA predicted by the machine learning model exhibits a good combination of biocompatibility and mechanical performance, attributed to a significant electron flow and charge recombination. This work reveals the importance of these strategies, combined with machine learning and first-principles calculations, on the development of advanced biocompatible HEAs.