Introduction: Medical education is proven to be associated with a high degree of psychological stress. Different coping strategies used by students have been investigated on their efficacy. So far, studies on medical students have been limited to a single population. Aim of the study: Our study aimed to identify differences in the prevalence of depressive symptoms, anxiety, stress levels, and defense mechanisms among two groups of medical students, the Polish and English-speaking divisions. Materials and methods: The study included two groups of first-year medical students, the Polish and English-speaking divisions, comprising 305 participants (n = 204 Polish, n = 101 English, men = 127, women = 176). It was divided into two periods: the students received author questionnaires during an exam-free academic period and then completed the same questionnaires during an exam session. The survey contained questions pertaining to demographics and studying habits among participants and included the Defense Style Questionnaire and Depression Anxiety Stress Scales. Data were analyzed using STATISTICA version 12.0, and p ≤ 0.05 was considered significant. Results: Polish medical students presented with significantly increased overall stress levels (p = 0.007858) and depressive symptoms (p = 0.030420) compared to the English division students. Polish students also presented with more symptoms of stress, depression, and anxiety during the exam period compared to the exam-free period (p = 0.000625), which did not apply to the English-speaking students. The English division students reached higher scores in the mature defense mechanisms section than the Polish students (p = 0.000001). The use of mature defense mechanisms correlated negatively with the intensity of stress, anxiety, and depressive symptoms in both groups, while immature defense mechanisms promoted higher values of those variables (p = 0.000001). Conclusions: Our study showed significant and multidirectional differences between medical students of the Polish and English divisions attending the same university. Such results could suggest that strategies aimed at reducing depressive symptoms among medical students ought to be adapted towards the needs of a specific population.