A combinatorial material synthesis and analysis method can offer a great promise of mapping the elasto-plastic and diffusion properties in refractory multi-element alloys of Ti-Nb-Zr-W system with various compositions. Six groups of Ti-Nb-Zr-W quaternary diffusion couples annealed at 1273 K for 25 h were prepared and measured by electron probe microanalysis and nanoindentation tests. Subsequently, the composition-dependent elasto-plastic properties in a wide composition range of Ti-Nb-Zr-W system were obtained by using two analytical methods including Oliver-Pharr analysis and reverse analysis algorithms. Moreover, elasto-plastic property and interdiffusion coefficient databanks of BCC Ti-Nb-Zr-W system were established by using the machine learning and pragmatic numerical inverse methods, respectively. A hot workability parameter defined by the ratio of Young’s modulus to main interdiffusion coefficient was proposed to evaluate the behavior during the hot working. Finally, wear resistance of refractory multi-element alloys was also discussed and verified by the experimental results. The results reveal that Ti-rich refractory multi-element alloys with the low W content have high hardness, good wear resistance, high stress, and excellent processability during the hot working, while the relatively high W content cannot improve the elasto-plastic properties of Ti-rich refractory alloys.