Fatigue life and reliability of aero-engine blade are always of important significance to flight safety. The establishment of damage model is one of the key factors in blade fatigue research. Conventional linear Miner’s sum method is not suitable for aero-engine because of its low accuracy. A back propagation neutral network (BPNN) based on the combination of Levenberg-Marquardt (LM) and finite element method (FEM) is used to describe process of nonlinear damage accumulation behavior in material and predict fatigue life of the blade. Fatigue tests of standard specimen made from TC4 are carried out to obtain material fatigue parameters and S-N curve. A nonlinear continuum damage model (CDM), based on the BPNN with one hidden layer and ten neurons, is built to investigate the nonlinear damage accumulation behavior, in which the results from the tests are used as training set. Comparing with linear models and previous nonlinear models, BPNN has the lowest calculation error in full load range. It has significant accuracy when the load is below 500 MPa. Especially, when the load is 350 MPa, the calculation error of the BPNN is only 0.4%. The accurate model of the blade is built by using 3D coordinate measurement technology. The loading cycle in fatigue analysis is defined from takeoff to cruise in 10 min, and the load history is obtained from finite element analysis (FEA). Then the fatigue life of the compressor blade is predicted by using the BPNN model. The final fatigue life of the aero-engine blade is 6.55×104 cycles (10 916 h) based on the BPNN model, which is effective for the virtual design of aero-engine blade.