BACKGROUND: Current interventions for major depressive disorder (MDD) are suboptimal, and only one third respond to them on initial treatment. Neuroplasticity theories are the basis for several emerging treatments. Evidence on the impact of yoga, a well-known mind-body intervention, on neuroplasticity in MDD is limited. OBJECTIVES: To determine the effects of 12-week yoga- and meditation-based lifestyle intervention (YMLI) on depression severity and systemic biomarkers of neuroplasticity in adult MDD patients on routine drug treatment. METHODS: A total of 58 MDD patients were randomized into yoga or control group. The severity of depression was assessed with Beck Depression Inventory-II scale (BDI-II). Blood samples were collected before and after intervention for the measurement of the biomarkers that characterize neuroplasticity, including mind-body communicative and cellular health biomarkers. RESULTS: There was a significant decrease [difference between means, (95% CI)] in BDI-II score [-5.83 (-7.27, -4.39), p < 0.001] and significant increase in BDNF (ng/ml) [5.48 (3.50, 7.46), p < 0.001] after YMLI compared to control group. YMLI significantly increased DHEAS, sirtuin 1, and telomerase activity levels, and decreased cortisol, and IL-6 levels, in addition to decreasing DNA damage and balancing oxidative stress. Multiple regression analyses were used to associate neuroplasticity biomarkers with depression severity. A 'post-intervention change in BDNF' x 'group' interaction indicated that yoga group had more BDNF in association with less BDI-II scores relative to controls. Increased sirtuin 1 and telomerase activity and decreased cortisol significantly predicted this association (all p < 0.05). CONCLUSION: These results suggest that decrease in depression severity after YMLI in MDD is associated with improved systemic biomarkers of neuroplasticity. Thus YMLI can be considered as a therapeutic intervention in MDD management.