TC4 titanium alloy (TC4) was vacuum diffusion welded to T2 copper (T2) with vanadium (V) foil as an interlayer. The influence of process parameters on elemental diffusion behavior, microstructure evolution, and shear performance of welded joints was explored. An obvious solid-solution diffusion zone appeared in the welded interface between TC4 and V, but no distinct diffusion zone formed in the joint interface of V/T2. The solid-solution phases of (Ti6, V)ss, (Ti3, V)ss, and (Ti, V7)ss appeared in the interface of TC4/V. The crystallographic orientations of (Ti6, V)ss, (Ti3, V)ss, and (Ti, V7)ss phases in high-resolution transmission electron microscope images were (002), (201), and (121), respectively. The lattice mismatch between (Ti6, V)ss and (Ti3, V)ss was calculated to be 11.9%. The activation energy to form a stable solid solution between titanium and vanadium was 226.6 kJ/mol. The highest shear strength of the welded joint reached 160 MPa, obtained at 860°C (1580°F) for 60 min. The joint fractured along the interface of V/T2, illustrating that the solid-solution structure between Ti and V was stronger than the metallurgical bonding between V and Cu. The fracture surface of the welded joints revealed a river pattern and ladder topography, representing a cleavage fracture mode. FCC-Cu, BCC-V, and β-Ti were detected on both fracture surfaces of the TC4 titanium alloy and T2 pure copper sides. The influence of welding temperature on the diffusion of V in Ti was greater than on Ti in V, and Ti and Cu diffused faster than V in the joint.