This cross-sectional study was aimed to compare happiness and depression levels among group Turkish and international medical students in Istanbul, Turkey. Data were collected through an online survey that included demographic inquiries, the Oxford Happiness Scale, and Beck’s Depression Inventory II. Significant contrasts emerged in demographic and lifestyle factors between Turkish and international students. Turkish medical students displayed a higher prevalence of unhappiness, although this difference was not statistically significant (66.3% for Turkish students vs. 59.1% for international students; χ² = 2.472, p = 0.116). Conversely, no marked differences were observed in the severity of depression between the two groups (χ² = 0.028, p = 0.986). Conversely, no marked differences were observed in the severity of depression between the two groups (χ2 = 0.028, p = 0.986). Logistic regression analyses revealed noteworthy associations. Factors such as age, academic phase, family history of psychiatric illness, and prior psychiatry treatment were linked to heightened odds of experiencing unhappiness among students. Similarly, significant predictors of depression included a family history of depression and prior psychiatry treatment. However; gender, age, relationship status, accommodation, alcohol consumption, smoking habits, and repeated academic years did not exhibit significant associations with unhappiness among the sampled medical students. While the models demonstrated modest explanatory power, these findings emphasize the urgent need to address mental health issues among medical students. Tailored interventions targeting specific vulnerable subgroups are crucial and further research is needed to identify additional factors contributing to psychological distress in this demographic.