An integrated experimental and simulation approach is proposed to study the effect of loading uncertainties on the fatigue crack growth behavior of Al 7075-T6. Various loading histories, including constant amplitude loadings, single overload block loadings, and deterministic and random variable spectrum loadings are used in the current investigation. Multiple specimen tests are performed and statistical analysis is used to extract the probability distribution of crack size and fatigue life. A previously developed small time scale model is used as a mechanism model to explain the fatigue crack growth behavior under random variable amplitude loadings. Monte Carlo simulation is used for the probabilistic fatigue life prediction. Model predictions are compared with the experimental observations for model validation. It is observed that the effect of uncertain loading is different under different loading spectra. For some cases, the uncertainties of loadings have no major impact on the probabilistic life distribution. For other cases, loading uncertainties have significant impact on the scattering of the life distribution. Model analysis indicates that this behavior is mainly due to the scattering of crack opening stresses produced under different variable amplitude loading spectra.