Objective Cajaninstilbene acid comprises a relatively high proportion of the stilbene in pigeon pea leaves and has significant anti-inflammatory and neuroprotective effects. This study aimed to observe the antidepressant effect of cajaninstilbene acid and explore its possible mechanism. Methods A mouse model of depression was established by chronic unpredictable mild stress (CUMS) and were treated with cajaninstilbene acid. A sucrose preference test was used to evaluate the degree of anhedonia and the serum corticosterone level was detected by ELISA. The concentrations of several neurotransmitters in the cortex and hippocampus were determined by LC-MS/ MS. Results Cajaninstilbene acid reversed the decreased sucrose preference and the increased serum corticosterone levels induced by CUMS. Compared with the control group, the levels of several neurotransmitters were significantly changed in the cortex and hippocampus of CUMS mice, regulated by cajaninstilbene acid. Conclusions Cajaninstilbene acid has antidepressant effects, which may be mediated by reducing serum corticosterone levels and regulating the levels of brain neurotransmitters.