The study presents a two-scale modeling approach allowing for an efficient fatigue strength evaluation on a macro scale considering a micro-mechanical defect characterization of a Carbon Fiber Reinforced Polymer (CFRP) material. The modeling approach integrates a macro model with the effective elastic properties from micro-mechanical simulations considering voids. This enables the analysis of defects’ influence on material fatigue strength using a probabilistic weakest link approach. A CFRP laminate with a cross-ply layup was investigated. Two simulation case studies demonstrate the effect of void content and size on the characteristic fatigue strength. An experimental investigation was conducted testing the laminates in tension–tension fatigue verifying the predicted numerical behavior. The numerical models identify a difference in the characteristic fatigue strength consistent with the fatigue test results. It is numerically concluded that the investigated CFRP material's fatigue strength is affected by the presence of voids and even with only a slight difference in the global void volume fraction a scatter in fatigue strength is identified.