Depression and related mood disorders are among the world’s greatest public health problems. Previous studies have demonstrated that astilbin (AST) has broad pharmacological functions which may modulate numerous pathways, such as antioxidant, scavenging free radicals, anti-inflammatory and so on, similarly to some of other flavonoids. In this study, the antidepressant-like effect of AST was investigated using chronic unpredictable mild stress (CUMS) model of depression in mice. The results showed that chronic administration of AST at doses of 10, 20 and 40 mg/kg (intraperitoneally (i.p.), 21 d) reduced depressive-like behaviors of mice in the forced swim test (FST), tail suspension test (TST) and sucrose preference test (SPT) without affecting locomotor activity. AST increased the contents of serotonin (5-HT) and dopamine (DA) in the frontal cortex of CUMS mice. Additionally, it was shown that AST treatment restored the CUMS-induced inhibition of extracellular signal-regulated kinase (ERK) 1/2 and AKT phosphorylation in the frontal cortex, conformed to the brain-derived neurotrophic factor (BDNF) expression. Our findings suggest that AST has antidepressant activities and the mechanisms, at least in part, relate to up-regulation of monoaminergic neurotransmitters (5-HT and DA) and activation of the BDNF signaling pathway.