Ti-6Al-4V(wt.%)/Ti-43Al-3V-2Cr(at.%) composite plates with no interfacial defects were successfully prepared by a high-reduction hot-rolling method. Microstructure and mechanical properties were studied. The experimental results show that no obvious defects in the interfacial region are observed, and the Kirkendall phenomenon is successfully avoided. The interface thickness of the composite plate is about 230 μm, according to different phase compositions, the interface is divided into two regions, one of which is near the interface of Ti6Al4V alloy and is mainly composed of α/α2 + β/B2 phase; Interface 2 is near the interface of TiAl alloy, and mainly consists of α/α2 + β/B2 + γ phase. The interface region structure is due to the diffusion of Ti element in Ti6Al4V alloy to TiAl alloy layer and the diffusion of Al and Cr elements from TiAl layer to Ti6Al4V alloy layer. The Vickers hardness and three-point flexural strength of the composite panels were tested with different loading methods. The experimental results show that the interface 1 has the highest microhardness, and the composite plate exhibits the best bending resistance when the surface of the transverse specimen is loaded, and the bending strength reaches 1150.82 MPa. The mechanical properties were analyzed and discussed in detail in combination with the microstructure characteristics.