An analysis has been made of the residual thermal stress of Nb2O5/Nb2O5-Ti/Ti multilayer coating on Ti6Al4V by adopting the finite element method, followed by a research and optimization of the influence of the number and thickness of the film layer and composition exponent of the Nb2O5-Ti gradient interlayers on the residual thermal stress. The results show that the maximum residual thermal stress decreases from 12.6 MPa to 11.7 MPa with the increase of gradient interlayers from 1 layer to 6 layers, but the maximum value of residual thermal stress undergoes no significant change with the number of gradient layers increasing to 8 layers. The thicker the gradient layer is, the smaller the maximum residual thermal stress will be. When the composition exponent increases from 0.5 to 3.0, the maximum residual thermal stress first decreases and then increases, and the maximum residual thermal stress (8.93 MPa) is the minimum with the composition exponent being 1.5. The optimal combination of structural parameters of the gradient layer of multilayer coating can be obtained by using the orthogonal test method, i.e., with the number of gradient layers being 7, the thickness of each gradient layer 1 μm, and the composition exponent 1.5. The maximum residual thermal stress of the optimized multilayer coating is 8.53 MPa, which is 59.2% and 61.4% lower than that of Nb2O5 monolayer (20.9 MPa) and Nb2O5/Ti bilayer coating (22.1 MPa), respectively.