Major depressive disorder (MDD) is a highly disabling psychiatric illness characterized by persistent low mood and psychomotor retardation, often leading to cognitive impairment or even suicidality. As the pathogenesis remains poorly understood, the currently available treatment regimens are mostly symptomatic therapies with little satisfactory curative effect. The emerging paradigm of gut-brain axis has highlighted gut dysbiosis as a key etiological factor to elicit neuro-inflammation and jeopardize the central nervous system homeostasis. In this study, we evaluated the ameliorating effects of flaxseed lignans on the gut microbiome to regain the gut micro-environmental functionality and alleviate MDD. The lignans significantly mitigated the severity of disease and markedly altered the gut microbiota structure in the participants. In the MDD mouse model, the lignans reversed the experimental depression-like behaviors, repaired neural and gut damage and restored barrier integrity. Of great significance, the lignans elevated the levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA), and markedly attenuated microglial and systemic inflammation. Mechanistically, the lignans inhibited the IL-17/AP-1/NF-κB axis through direct interaction with the Fos protein. In the BV-2 cells, the lignan enterolactone reduced levels of nitric oxide and pro-inflammatory cytokines, further validating the anti-inflammatory mechanism of the lignans. Together, these findings demonstrate that lignans exert potent antidepressant effects by modulating the gut-brain axis and resolving neuro-inflammation, providing useful information for the development of novel therapeutic strategies for MDD prevention and treatment.