This paper proposes a performance-based mix design (PBMD) framework to support performance-related specifications (PRS) needed to establish relationships between acceptable quality characteristics (AQCs) and predicted performance, as well as to develop fatigue-preferred, rutting-preferred, and performance-balanced mix designs. The framework includes defining performance tests and threshold values, developing asphalt mix designs, identifying available performance levels, conducting sensitivity analysis, establishing the relationships between AQCs and predicted performance, and determining performance targets and AQC values for the three PBMDs using predicted performance criteria. Additionally, the framework recommends selecting the PBMD category for each asphalt layer to minimize pavement distresses. In this study, the proposed PBMD protocol was applied to FHWA accelerated loading facility (ALF) materials using asphalt mixture performance tester (AMPT) equipment coupled with mechanistic models. The study developed nine mix designs with varying design VMAs and air voids using the Bailey method. The cracking and rutting performance of the mix designs were determined by direct tension cyclic (DTC) fatigue testing, triaxial stress sweep (TSS) testing, and viscoelastic continuum damage (S-VECD) and viscoplastic shift models for temperature and stress effects. The study found that adjusting the design VMA was the primary way to achieve required performance targets. For fatigue-preferred mix design, the recommended targets were a cracking area of 0 to 1.9%, a rut depth of 10 mm, and a design VMA of 14.6 to 17.6%. For rutting-preferred mix design, the recommended targets were a cracking area of 18%, a rut depth of 0 to 3.8 mm, and a design VMA of 10.1 to 13.1%. For performance-balanced mix design, the recommended targets were a cracking area of 8.1 to 10.7%, a rut depth of 4.6 to 6.4 mm, and a design VMA of 12.6 to 14.3%. Finally, pavement simulation results verified that the proposed PBMD pavement design with fatigue-preferred mix in the bottom layer, performance-balanced mix in the intermediate layer, and rutting-preferred mix in the surface mix could minimize bottom-up cracking propagation without exceeding the proposed rutting performance criterion for long-life.