The mix design for hot in-place recycled mixtures is the key that determines the regeneration performance of asphalt pavement. However, existing design methods have numerous problems, such as the involvement of numerous influential factors and levels and poor adaptation to the composition features of hot in-place recycled mixtures. To establish a mix design method for hot in-place recycled mixtures, the mode of action of rejuvenator was analyzed in this study, and the mix design method for mixtures was optimized by introducing an orthogonal test. The regeneration mechanism of rejuvenators in reclaimed asphalt pavement (RAP) was analyzed, and the optimal working conditions of rejuvenators were determined preliminarily through physical performance, chemical composition, and dynamic shearing rheological tests. In addition, the influences of the dosage of rejuvenator, RAP, and new asphalt on the high-temperature and low-temperature performance and water stability of the recycled asphalt mixture were analyzed through an orthogonal design method by combining trabecular bending rheological, wheel rutting, and freeze-thaw splitting tests. The optimal mix design of the recycled mixture was determined on this basis. According to test results, the rejuvenator and RAP can influence the pavement performance of the recycled mixture more than new asphalt. When the dosage of the rejuvenator is 5% of the total asphalt mass, the proportion of RAP and new asphalt are 80% and 0%, respectively, and the recycling effect of the asphalt mixture is the best. The proposed method is economical and environmentally friendly and has been well applied in ordinary trunk highway maintenance engineering in Hanzhong City, Shaanxi Province, China, since 2017. Research conclusions can provide references for the hot in-place recycling engineering of asphalt pavement. Keywords: Hot in-place recycling, Rejuvenator dosage, RAP, Dynamic shear rheological test, Orthogonal test