The utilization of waste polyethylene terephthalate (WPET) as aggregate substitutes in pavement has been extensively promoted because of its environmental advantages. However, previous studies have shown that a high percentage of WPET reduces the performance of the pavement. To increase the durability of pavement and mitigate the environmental issues caused by WPET, WPET is treated with gamma-irradiation as a component in asphalt mixtures. The study objectives were to investigate the feasibility of using WPET granules as a sustainable aggregate on asphalt mixture stiffness and rutting and predict the asphalt mixture performance containing irradiated WPET via an RSM-ANN-framework. To achieve the objectives, stiffness and rutting tests were conducted to evaluate the WPET modified mixtures� performance. The result indicated that samples containing 40 irradiated WPET provided a better performance compared to mixtures containing 20 non-irradiated WPET, increasing the stiffness by 27 and 21 at 25�C and 40�C, respectively, and rutting resistance by 11 at 45�C. Furthermore, both predictive models developed demonstrated excellent reliability. The ANN exhibited superior performance than the RSM. The utilization of WPET as aggregate in asphalt mixtures represents a way to addressing related recycling issues while also improving performance. With gamma-irradiation treatment, the utilization of WPET can be increased with improved asphalt mixture performance. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.