Introduction and objectives: Burnout Syndrome (BS) has been evaluated in few populations of medical students, and its relationship with depression is even less studied. The objective was to determine the frequency of BS in medical students of the Universidad Pedagógica y Tecnológica de Colombia (UPTC), in Tunja, Colombia, as well as its association with depression and other social, economic, demographic, and academic factors. Methods: An observational, analytical, cross-sectional study was carried out on 182 UPTC medical students during 2018. The Maslach Burnout Inventory-Student Survey (MBI-SS) was applied, with which 3 components were obtained to determine positive SB. This was crossed in the Stata 15 program for depression and other social, economic, demographic, and academic covariates with the Generalised Linear Model (GLM). Results: Of 182 respondents, 51.4% were women. The median age was 21 years (20-23 years). 14% had BS, of which 48% had depression. In the multiple regression, BS was significantly associated with a higher frequency of depression (RPa = 5.54; IC95%, 2.36-13.02; P < 0.001) and the feeling of insufficient money (RPa = 4.37; IC95%, 1.95-9.83; P < 0.001), in contrast to a negative association with smoking (RPa = 0.13; IC95%, 0.06-0.30; P < 0.001) and being a woman (RPa = 0.32; IC95%, 0.12-0.82; P = 0.018). The age of onset of marijuana use was not significant. Conclusions: BS shows a high association with increased depression and a feeling that the money is not enough at the end of the month, but it showed a negative association with tobacco consumption and being a woman. Such students should be detected to provide them with adequate academic support.