When prolonged, excessive training stresses are applied concurrent with inadequate recovery, performance decrements and chronic maladaptations occur. Known as the overtraining syndrome (OTS), this complex condition afflicts a large percentage of athletes at least once during their careers. There is no objective biomarker for OTS and the underlying mechanism is unknown. However, it is not widely recognised that OTS and clinical depression [e.g. major depression (MD)] involve remarkably similar signs and symptoms, brain structures, neurotransmitters, endocrine pathways and immune responses. We propose that OTS and MD have similar aetiologies. Our examination of numerous shared characteristics offers insights into the mechanism of OTS and encourages testable experimental hypotheses. Novel recommendations are proposed for the treatment of overtrained athletes with antidepressant medications, and guidelines are provided for psychological counselling.