This study investigates the influence of curriculum design on university students’ academic performance in Cambodian higher education, emphasizing the mediating role of self-regulation. A quantitative research design was adopted, collecting data from 320 lecturers across public and private universities. Using SmartPLS (PLS-SEM), the measurement model demonstrated strong reliability (Cronbach’s α > 0.90) and validity (AVE > 0.60). The structural model explained 15.6% of the variance in self-regulation and 11.8% in students’ performance, with Q² values above zero, confirming predictive relevance. Curriculum design did not significantly affect students’ performance directly (β = 0.099, t = 1.655, p = 0.099) but had a strong positive effect on self-regulation (β = 0.405, t = 8.580, p = 0.000). Self-regulation significantly enhanced students’ performance (β = 0.296, t = 5.420, p = 0.000) and mediated the relationship between curriculum design and students’ performance (β = 0.120, t = 4.370, p = 0.000). The results suggest that curriculum design indirectly improves academic outcomes by fostering self-regulatory skills. These findings highlight the need for learner-centered, goal-oriented curricula that actively cultivate self-regulation, empowering students to manage their learning processes and achieve better academic performance.