Background: Stress is an inevitable event in a medical student's life, especially during the clinical years. Overwhelming stress has a negative impact on student's mental health and academic performance. Objectives: To assess the perceived stress levels among medical students, identify the primary stressors, and explore the relationship between stress, academic performance, and socio-demographic factors. Subjects and Methods: This cross-sectional observational study included 240 medical students from the academic year 2020/2021. Data collection involved socio-demographic and academic information, the Perceived Stress Scale (PSS), the Medical Student Stress Questionnaire, and the Brief COPE scale. Results: A substantial 89.3% of students experienced moderate to high stress levels (Mean ± SD: 27.83 ± 6.3). Female students reported significantly higher stress levels than males (p < 0.01). The primary sources of stress were academic-related (70.4%) and teaching and learning-related (48.75%). Adaptive coping was used by 66.7% of students. There was a significant negative correlation between PSS scores and both GPA and adaptive coping strategies. Predictors of higher stress levels included lower GPA (B= -2.72, p= 0.003), being female (B= -2.4, p= 0.05), academic-related stressors (B= 0.219, p= 0.001), interpersonal-related stressors (B= 0.154, p= 0.05), daily-related stressors (B= 0.478, p= 0.04), and adaptive coping (B= -0.388, p= 0.00). Conclusion: This study document high stress level among medical students in Jazan University. There is a strong need for establishing students counseling program (academic and psychological), curricular modification, and improving facilities for recreational activities.