Background <p>The overall well-being and academic performance of university students are profoundly influenced by their sleep patterns and mental health. This study aimed to compare levels of stress, anxiety, depression, and sleep quality between medical and non-medical students at Mansoura University.</p> Methods <p>In the academic year 2023–2024, a comparative cross-sectional descriptive study with an analytical component was conducted at Mansoura University. A total of 322 medical students and 354 non-medical students from the Faculty of Commerce were recruited through convenience sampling. Data were collected via a structured survey that included the Depression Anxiety Stress Scales-21 (DASS-21) and the Pittsburgh Sleep Quality Index (PSQI). Statistical analysis was performed using SPSS version 26, with chi-square tests and logistic regression to identify predictors of poor sleep quality.</p> Results <p>Medical students had significantly worse outcomes in both mental health and sleep quality compared with non-medical students. Poor sleep quality was more common among medical students (83.2%) than non-medical students (63.8%, <i>p</i> &lt; 0.001). Higher proportions of medical students reported moderate to severe depression (43.5% vs. 15.3%), anxiety (40.1% vs. 12.4%), and stress (46.3% vs. 16.9%), all <i>p</i> &lt; 0.001. Multivariate logistic regression showed that depression, anxiety, and stress were significant predictors of poor sleep quality. Medical students had a higher likelihood of poor sleep quality than non-medical students (OR = 1.9, 95% CI: 1.2–3.2). Severe to extremely severe anxiety was the strongest predictor (OR = 6.8, 95% CI: 2.9–16.2).</p> Conclusions <p>Medical students showed a higher prevalence of poor sleep; however, this difference may partly reflect underlying sociodemographic differences. These findings highlight the need for targeted interventions to improve sleep quality and mental health support for students, particularly in demanding programs such as medicine.</p>