In order to reveal the effect of homogenization treatment on the phase composition and chemical distribution of MoNbTa-based refractory multi-component alloys, the microstructures and mechanical properties of as-cast and homogenized (MoNbTa)6TixVy (x + y = 4) alloys were investigated by using X-ray diffraction, scanning electron microscopy and mechanics performance tests. Besides, the theoretical elastic properties and bonding behavior were analyzed by the first principle calculations. The results show that except for (MoNbTa)6Ti2.5V1.5 alloy, there are no obvious differences of crystal structures between other as-cast and homogenizing alloys. The lattice constants of (MoNbTa)6TixVy alloys increase with the increase of Ti content, while the lattice constants of alloys decrease after homogenization treatment. Typically (Mo, Ta)-rich dendritic and (Ti, V)-rich interdendritic morphologies are observed, and the atoms would diffuse during the homogenization process resulting in the uniform composition. The as-cast (MoNbTa)6Ti2V2 alloy exhibit the largest values of compressive strength, plasticity, and hardness in these alloys. Following homogenization, the mechanical properties of (MoNbTa)6TixVy alloys decrease significantly. The results of first principles reveal that the covalent bonding interactions between Ti and V atoms are stronger than that between Mo and Ta atoms in these MoNbTa-based refractory multi-component alloys.