University students face various stressors related to academics, personal issues, and their environment. This stress can negatively impact health-related quality of life (HRQOL). This study aimed to explore stressors influencing Palestinian dentistry students at Arab American University and their relationship with HRQOL. A cross-sectional survey was conducted among 232 undergraduate dentistry students using a comprehensive 46-item questionnaire. Stressors across,individual, academic, faculty, and institutional domains were measured. HRQOL was assessed across psychological, occupational, , personal and social, physical, and religious and spiritual domains (63 items). Data analysis included descriptive statistics, correlation analysis, and regression modeling. Key stressors included academic workload, facultyrelations, clinical training, and social adjustment. These significantly correlated with poorer HRQOL, especially psychological wellbeing and academic performance. Regression analysis found higher anxiety, time management difficulties, instructor attitude, and dietary changes as top predictors of reduced HRQOL. Palestinian dentistry students face multifaceted stressors that profoundly impact HRQOL. A supportive educational environment encompassing counseling services, mentorship programs, stress management training, and student-centered policies is crucial. This study highlights specific stressors affecting an under-researched population, guiding context-appropriate interventions to improve wellbeing and academic outcomes.