In this study, a method of introducing an Nb intermediate layer added by tungsten inert gas welding was proposed and used in the fabrication of a crack-free Ti6Al4V/Al6.21Cu bimetallic structure by wire and arc additive manufacturing (WAAM) based on cold metal transfer (CMT) technique. The results showed that the addition of an Nb interlayer between Ti6Al4V and Al6.21Cu could effectively impede the diffusion of Ti and Al elements, thereby inhibiting the formation of Ti-Al brittle intermetallic compounds. The reaction layer composed of Al3Nb was formed at the Al6.21Cu/Nb interface. The average ultimate tensile strength of the Ti6Al4V/Al6.21Cu bimetallic structure with and without Nb interlayer were 120.9 MPa and 94.5 MPa respectively, indicating that the addition of Nb interlayer can significantly improve the mechanical properties of the Ti6Al4V/Al6.21Cu bimetallic structure.