In recent years, human-nature interactions are becoming a fundamental issue. Indeed, spending time in nature reduces stress and promotes mental well-being; however, the underlying biological mechanisms of action are still elusive. Major depressive disorder (MDD), one of the most prevalent and debilitating psychiatric diseases, is characterized by severe symptoms that negatively influence health perception. Unfortunately, even after antidepressant treatments, a high percentage of patients do not achieve a personal full recovery. Therefore, we decided to i) evaluate the biological, molecular and epigenetic impact of spending time in the greenery on MDD patients, and ii) highlight the importance of urban “green-therapy” on depressive symptoms. For this purpose, we enrolled MDD patients (recommended to walk regularly in urban parks, at least 40 minutes 3/4 times per week, for 6 months) and healthy control subjects. Then, we evaluated serological markers of inflammation (e.g. cortisol, CRP, IL-6) and epigenetic markers (i.e. miRNAs and post-translationally modified histone proteins) that correlate with MDD. Our results, in MDD patients, over time (from baseline to 6 months), after “green-therapy”, clearly show that: IL-6 level significantly decreases returning to healthy control levels; the expression of the tested miRNAs seems to be completely restored in PBMCs; the levels of some post-translational modified histone proteins analysed in PBMCs are significantly restored. Therefore, we provide new scientific evidence about beneficial effects of green environment on depressive symptoms, and propose greenness-related activities as a potential combinatorial treatment to reduce pharmacological administration and achieve a personal full recovery.