Sesamin, a lignan from sesame seed, has been reported to attenuate chronic mild stress-induced depressive-like behaviors. Gut microbiota play pivotal roles in mediating psychological behaviors by regulating gut barrier integrity and systemic inflammatory responses. Here, we found that oral sesamin administration (50 mg/kg·bodyweight/day) significantly attenuated depressive, aversive, repetitive, and anxiety-like behaviors in a long-term multiple nonsocial stress-treated mice model. Sesamin inhibited stress-induced gut barrier integrity damage, reduced circulating lipopolysaccharide (LPS) levels, and suppressed neuroinflammatory responses. Moreover, sesamin treatment also restructured the gut microbiome by enhancing the relative abundances of Bacteroidales and S24-7. The correlation analysis indicated that the microbiota composition changes were strongly correlated with behavioral disorders, serotonin, norepinephrine, and LPS levels. In conclusion, sesamin has preventive effects on stress-induced behavioral and psychological disorders, which might be highly related to the reshaped microbiota composition. This study provides a clue for understanding the systemic mechanism of anti-depression effects of sesamin.