Rationale <p>Adolescent depression is often linked to biological changes associated with stress. However, new approaches and treatment strategies for early intervention and prevention of depression in children and adolescents are still limited. Ashwagandha is an Ayurvedic herb widely used in the management of anxiety and stress. However, there is no information in the current literature on its potential effect on adolescent depression.</p> Objectives <p>This study aimed to investigate the effects of depression on proapoptotic proteins and neuroinflammation and the antidepressant effect of Ashwagandha on depression-like symptoms in adolescent rats exposed to the Chronic Unpredictable Mild Stress (CUMS) model.</p> Methods <p>In the study, CUMS model was used to induce depression in adolescent rats. Rats were treated with Ashwagandha or Sertraline. To evaluate the antidepressant effects, behavioral tests as well as biochemical and histological analyses were performed. Forced Swim Test (FST), Sucrose Test and Elevated Plus Maze Test were performed as behavioral tests. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured by the ELISA method in the fronto-parietal cortex. Proapoptotic proteins (Bax and Caspase-3) and inflammatory markers (TNF-α and IL-1β), as well as glial fibrillary acidic protein (GFAP), were evaluated immunohistochemically in the fronto-parietal cortex.</p> Results <p>Proapoptotic proteins (Bax and Caspase-3) and inflammatory markers (TNF-α and IL-1β) were increased in the CUMS group. BDNF and GFAP levels were decreased. Ashwagandha treatment was more effective than Sertraline in reducing the levels of these proteins and markers. Additionally, Ashwagandha prevented weight loss.</p> Conclusions <p>Ashwagandha showed antidepressant-like effects in adolescent rats, reducing apoptosis, inflammation, and neuroinflammation, suggesting potential for treating adolescent depression.</p> Graphical Abstract <p></p>