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Depression is the most common behavior disorder that leads to many disabilities. The main aim of this study was to evaluate the effects of a <i>Polygonum minus (P. minus)</i> aqueous extract on chronic ultra-mild stress (CUMS)-induced depressive mice model. Chronic ultra-mild stress can disturb the neurotransmitters levels and plasticity of the hippocampus. Balb/c male mice were used in this study, which consisted of six groups (<i>n</i> = 14). Treatment was given for eight weeks, and chronic ultra-mild stress was applied for six weeks. Commercially available <i>P. minus</i> extract (BioKesum^®) was used in this study. The behavior and neurochemical parameters were investigated through behavioral Tests and ELISA assays. <i>P. minus</i> administration significantly <i>(p <</i> 0.05) restored CUMS-induced behavior abnormalities, decreased the immobility time, and increased the sucrose preference and increased the spatial memory. <i>P. minus</i> treatment also showed the decreased level of serum corticosterone and increased the level of hippocampal neurotransmitters (Serotonin and Norepinephrine) significantly <i>(p <</i> 0.05). The brain-derived neurotrophic factor (BDNF) level also increased significantly in both the prefrontal cortex and hippocampus <i>(p <</i> 0.05). <i>P. minus</i> treatment exhibited significant (<i>p <</i> 0.05) reduction of Monoamine Oxidase-A (MAO-A) in the hippocampus. These findings indicate that <i>P. minus</i> aqueous extract exhibits antidepressant effects, including decreased immobility time, increased spatial memory, reduced corticosterone, increased BDNF level, and reduced MAO-A enzyme level with increasing the monoamines (serotonin and norepinephrine) in the hippocampus.