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The study aimed to assess the effect of chronic diseases on health-related quality of life (HRQoL) among university students. A cross-sectional analytic study was conducted at King Abdulaziz University, involving 1173 students. Questionnaire on chronic diseases, HRQoL using the 36-item Short Form Health Survey (SF-36), alongside other factors was distributed electronically. Regression analysis was used to identify factors associated with HRQoL. The mean ± SD scores across SF-36 dimensions varied, with physical functioning scoring the highest (74.81 ± 27.82) and energy/fatigue the lowest (38.52 ± 24.03). The physical and mental component summary scores were 68.07 ± 18.67 and 49.20 ± 23.17, respectively. The study found a 23.1% prevalence of multimorbidity. Multimorbidity was associated with significantly lower HRQoL across all dimensions. Female sex, low family income, and lack of exercise were predictors of poor HRQoL. High-impact diseases were strongly associated with poorer physical health. The study revealed significant burden of multimorbidity that demands targeted interventions. Focus on modifiable risk factors, such as exercise and socioeconomic support, could enhance overall well-being and prevent negative health outcomes.