Formation of the W2Zr intermetallic is the key reason for the low relative density and brittleness of W-Zr alloys. In this study, 65W-Zr-Ti-Nb alloys with different Ti and Nb content were prepared by powder metallurgy. With the increase of Ti and Nb content, the proportion of the W2Zr in the alloy decreases, causing the densification of 65W-Zr-Ti-Nb alloys. The thermodynamic calculation shows that the addition of both Ti and Nb results in a narrowing stabilized temperature range of W2Zr and an expanding stabilized temperature range of BCC-WTixNby, respectively, ultimately causing the disappearance of the W2Zr and formation of the WTixNby during non-equilibrium cooling. Both high ductility and strength can be achieved in the W-Zr-Ti-Nb alloys by assistance of the disappearance of the brittle W2Zr phase and the formation of the ductility WTixNby. The first principle calculation indicates that the co-doping Ti and Nb results in a larger expansion on the spacing of the {110} close-packed plane and a smaller expansion or even shrinkage on the atomic spacing along the close-packed direction of the WTixNby. Further, integrated crystal orbital Hamilton population (ICOHP) results proved that the bonding strength of W-Ti and W-Nb was weaker than that of W-W in WTixNby. Both increased spacing of {110} plane and decreased interatomic bonding strength aid in reducing Peierls-Nabarro stress, promoting plastic deformation. This study provides a new method for improving mechanical properties by tailoring the phase constitution in W-Zr alloys through co-doping Ti and Nb.