MoSi2 is one of the most promising refractory metal silicide materials, but its further use as a structural material is limited by its drawbacks such as poor room-temperature toughness and low high-temperature strength. The work performed a comprehensive investigation combining first-principles calculations and arc cladding experiments to explore the effects of Nb and W doping on the mechanical properties and electronic structure of MoSi2 coatings. The first-principles calculations revealed that Nb addition improved the B/G value and Poisson's ratio of MoSi2, indicating enhanced ductility. W addition yields the opposite effect and led to a higher elastic modulus and improved hardness. Experimental results demonstrated that the arc-cladding MoSi2 coating mainly consisted of MoSi2 and Mo5Si3 phases with a dendritic microstructure. Upon doping with Nb and W, additional t-(Mo,Nb)Si2 and t-(Mo,W)Si2 phases were formed, which resulted in a denser and finer microstructure. Nb addition contributed to the solid-solution toughening of the coating, while W addition enhanced hardness but reduced toughness. Remarkably, the synergistic alloying of Nb and W significantly increased the hardness and fracture toughness of the coating by 30.7 and 70.7%, respectively, compared to pure MoSi2. The strengthening mechanism of the coating was attributed to solid-solution softening and fine-grain strengthening, while the crack extension mechanism involved the crack deflection and bridging. Furthermore, the coatings doped with 2% Nb and 4% W exhibited the lowest wear weight loss and superior wear resistance. The dominant wear mechanisms were oxidation wear and abrasive wear.