Currently, the viscoelastic properties of conventional asphalt cement need to be improved to meet the increasing demands caused by larger traffic loads, increased stress, and changing environmental conditions. Thus, using modifiers is suggested. Furthermore, the Sustainable Development Goals (SDGs) promote using waste materials and new technologies in asphalt pavement technology. The present study aims to fill this gap by investigating the use of pulverized oil palm industry clinker (POPIC) as an asphalt–cement modifier to improve the fatigue life of bituminous concrete using an innovative prediction approach. Thus, this study proposes an approach that integrates statistically based machine learning approaches and investigates the effects of applied stress and temperature on the fatigue life of POPIC-modified bituminous concrete. POPIC-modified bituminous concrete (POPIC-MBC) is produced from a standard Marshall mix. The interactions between POPIC concentration, stress, and temperature were optimized using response surface methodology (RSM), resulting in 7.5% POPIC, 11.7 °C, and 0.2 MPa as the optimum parameters for fatigue life. To improve the prediction accuracy and robustness of the results, RSM and ANN models were used and analyzed using MATLAB and JMP Pro, respectively. The performance of the developed model was assessed using the coefficient of determination (R2), root mean square error (RMSE), and mean relative error (MRE). The study found that using RSM, MATLAB, and JMP Pro resulted in a comprehensive analysis. MATLAB achieved an R² value of 0.9844, RMSE of 3.094, and MRE of 312.427, and JMP Pro achieved an R² value of 0.998, RMSE of 1.245, and MRE of 126.243, demonstrating higher prediction accuracy and superior performance than RSM, which had an R² value of 0.979, RMSE of 3.757, and MRE of 357.846. Further validation with parity, Taylor, and violin plots demonstrates that both models have good prediction accuracy, with the JMP Pro ANN model outperforming in terms of accuracy and alignment. This demonstrates the machine learning approach’s efficiency in analyzing the fatigue life of POPIC-MBC, revealing it to be a useful tool for future research and practical applications. Furthermore, the study reveals that the innovative approach adopted and POPIC modifier, obtained from biomass waste, meets zero-waste and circular bioeconomy goals, contributing to the UN’s SDGs 9, 11, 12, and 13.