The paper presents a methodology to carry out the series system reliability analysis of multilayered flexible pavements with respect to correlated fatigue and rutting failure modes. The importance of assessing the uncertainty associated with the random variables, which are the layer thicknesses and material properties, used in pavement designs was discussed. The variability associated with layer thicknesses and resilient moduli was incorporated into the design by performing component and system reliability analysis with correlated failure modes. Robust nonlinear regression equations which were proposed recently were used to relate the fatigue and rutting strains to the thickness and resilient moduli of the four layered flexible pavements. The first-order reliability method (FORM) was used to evaluate the component reliability indexes against fatigue and rutting failure modes. The overall performance of the pavement system was assessed using series system reliability analysis considering the simultaneous occurrence of both failure modes. A high variation in the degree of correlation between-0.02 and 0.90, was observed between fatigue and rutting modes. The sensitivity of layer thicknesses and corresponding resilient moduli on the performance of a pavement system was presented. The mean values of thicknesses and resilient moduli of bituminous, base, and subbase layers; resilient modulus of subgrade; and coefficients of variation of bituminous layer thickness (h1) and resilient modulus of subbase layer (Mr3) were found to predominantly influence the pavement system performance. The design values of resilient moduli and thicknesses of bituminous, base, and subbase layers to meet a desired system reliability level were presented in the form of design charts. A comparative study with existing design methods was presented, accounting the variability in pavement designs. The proposed system reliability-based design optimization (SRBDO) helps to improve the robustness and reliability of existing flexible pavement designs. © 2020 American Society of Civil Engineers.