Introduction. The medical course is extremely stimulating but also demanding, and it can interfere with students’ mental health. Stress leads to lower life quality, academic performance, and ultimately to a lower quality of patient care delivered. Objective. To analyse stress levels of sixth-year medical students who attend Portuguese colleges. Methodology. This observational cross-sectional study involved Portuguese medical students attending the sixth year of all Portuguese faculties. We applied an online self-response questionnaire, including the 10 items Perceived Stress Scale (PSS) to assess stress levels and sociodemographic variables. Logistic regression was used to estimate the weight of the studied determinants on stress levels. Results. A total of 501 participants were included for analysis (69.5% females), with a median age of 24 years old. We found significant levels of stress in 49.9% (95% CI: 45.5–54.3%), with 20.8% of total students presenting extremely high levels, irrespective of age, gender, and faculty. Stress was higher when students presented bad sleeping and eating habits, lack of ability to manage time, dissatisfaction with social life and academic experience, and low family support. Also, these students are more worried about their future and present a higher degree of concern about their graduation test performance. Conclusion. This study found high stress levels among Portuguese medical students, associated with social determinants and the intrinsic complexity of the course. This is worrying, and it elucidates the importance of coping strategies to make students deal with stress and be healthier, currently and in the future.