Abstract Objective Depression is Jordan’s most ravaging mental illness. Despite the growth of antidepressant use, only a handful of studies examine the factors affecting antidepressant knowledge among healthcare workers or medical students. Therefore, we aimed to explore the knowledge and attitudes towards antidepressants across Jordan’s six medical schools. Methods Using a cross-sectional design, we investigated the knowledge and attitudes towards antidepressants through the Drug Attitude Inventory and a literature-validated knowledge domain. Clinical students from Jordan’s six medical schools were recruited. Differences in knowledge and attitudes scores were examined by year of study, medical school among other factors. A multivariate linear regression model was utilized to assess predictors of knowledge. Results We included a total of 1,234 participants representing Jordan’s six major schools of medicine. About 14.9% of participants had a personal history of antidepressant use while 20.5% reported family history of psychiatric disease. The majority of students demonstrated favorable attitudes towards antidepressants (74.1%). Students demonstrated an average understanding of antidepressants’ mechanism of action, side effects, but not indications in special populations. Senior medical students, higher GPA, higher family income, personal history of antidepressants, and family history of psychiatric illnesses were associated with significantly higher knowledge scores (all p-values