Angelica keiskei is currently used as a popular functional food with various beneficial effects, including antioxidant, anti-obesity, anti-tumor, anti-diabetic, and anti-bacterial. A recent in vitro study reported that A. keiskei inhibits monoamine oxidases (MAOs), suggesting the antidepressant property of A. keiskei. However, in vivo studies on laboratory animals subjected to psychosocial stress have not been conducted. In this study, the effects of an A. keiskei leaves extract (AKE) on rats undergoing chronic social overcrowding stress were explored. Six-month-old male and female Wistar rats were housed in groups of three in 12 x 12 x 18 cm cages (overcrowding) for twenty-eight days. Both male and female rats were divided into two groups (N = 10); control group received oral distilled water, whilst the other group (treatment group) received 20 mg/kgBW/day of AKE supplementation. The results showed that AKE-treated rats exhibited lower anxiety- and depressive-related behaviors than that of control stressed rats. AKE significantly decreased corticosterone and increased testosterone and estrogen levels in stressed rats. Additionally, brain tissue MDA and TNF-alpha levels were reduced, while brain neurotransmitter 5-HT and antioxidant SOD levels were elevated by the AKE. These findings suggest, for the first time, that AKE could alleviate overcrowding stress-induced behavioral, neuroendocrine, antioxidant, and inflammatory dysfunctions. A. keiskei leaves extract could potentially be used as an agonist to reduce stress and depression.