The process of reaction kinetics was investigated for vacuum diffusion bonding of Ti2AlNb and GH4169 by inserting metal foils of Ni+Nb as interlayer. The results show that there is an optimum thickness (about 3.36 μm) for the reaction layer Ni6Nb7, which is the main factor that influences the joint’s shear strength. The modified effective heat of formation (MEHF) theory and the effective Gibbs free energy theory were applied to predict that Ni6Nb7 is the primary phase formed during Ni-Nb interface reaction, i.e., Ni6Nb7 phase inevitably forms during the bonding process. The growth rate of Ni6Nb7 layer is lower than that of Ni3Nb layer. Thus it is possible to control the thickness of Ni6Nb7 layer by optimizing the processing parameters so as to improve the mechanical properties of the joints. The optimized duration time for the samples bonded at 1050 oC under 20 MPa is 49.5 min. This condition issues experimental shear strength of the joint as 468.2 MPa.