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[Display omitted] • PSP attenuate depression-like behaviors in the chronic unpredictable mild stress (CUMS)-induced mice. • PSP normalize the dysfunction of the HPA axis and inhibit neuroinflammation. • PSP reverse the dysfunction of hormone release in the serum. • PSP restructured gut microbiome and the levels of short-chain fatty acids. Polygonum sibiricum polysaccharides (PSP) are one of the main active components of Polygonatum sibiricum. The present study was performed to deeply explore the antidepressant-like effects of PSP on the chronic unpredictable mild stress (CUMS)-induced depression and underlying mechanisms. PSP markedly reversed the depression-like behavior and significantly increased the levels of 5-hydroxytryptamine and norepinephrine, decreased the levels of the pro-inflammatory cytokines in the hippocampus and the corticosterone and adrenocorticotropic-hormone in the serum of CUMS-induced mice. Gut microbiota dysbiosis focusing on Bacteroidetes and Firmicutes and changes of SCFAs especially for butyrate, propionate and acetate were remarkably reversed by PSP. These findings indicated that the antidepressant-like effects of PSP were related to inhibit the HPA axis hyperactivation, normalize the neurotransmitter levels, suppress the neuroinflammation, regulate the composition of gut microbiota and the levels of SCFAs. The current study provides a new insight into the potential of PSP in prevention and treatment of depression. [ABSTRACT FROM AUTHOR]