An anti-fatigue and safety control method for ultra-long life service structures under extreme environment, comprising: judge the fatigue fracture mode in the long life stage of the service structure; according to the interaction principle of defect-matrix, obtain the internal defect induced fatigue cracking mechanism in ultra-high cycle regime under the service environment; considering the environmental factors, clarify the internal defect-matrix-environment interaction mechanism under service conditions and obtain the environmental weakening coefficient; considering the environmental factors, establish a fatigue life prediction model based on defect-load-life correlation under service conditions in ultra-high cycle regime; the process parameters of material metallurgy and manufacturing, design parameters of structural strength, structural service stress and environmental parameters are regulated based on the concept of integrated design/manufacturing.