Very high cycle fatigue (VHCF) tests were carried out under variable amplitude loading for TC21 titanium alloy. The first level of high amplitude loading was set as 950 MPa close to yield strength, and the second level of low amplitude loading was determined between 435 MPa and 500 MPa where fatigue cracks initiated at the specimen subsurface under constant amplitude. The results indicate that the high/low stress block significantly reduced the cumulative fatigue life of low stress amplitude, and the fatigue crack initiation site changed from the specimen subsurface under constant loading to the specimen surface under stress block. Based on continuum damage mechanics, the fatigue damage model of two-step stress block was established to estimate the fatigue damage process. The prediction of cumulative fatigue life generally agreed with the experimental data. The cumulative fatigue damage of the stress block was related to the stress amplitude and the cycle ratio, which determined the stress fatigue damage and its interaction damage. The surface crack initiation in the stress block accelerated fatigue damage of low stress amplitude, reducing the cumulative life.