Rats were subjected to unpredictable chronic stress and isolation-induced depression, and were then intragastrically perfused with Jieyu No.1 decoction or amitriptyline water solution for 21 consecutive days. Open-field test showed that Jieyu No.1 decoction and amitriptyline water solution significantly improved the abnormal behaviors of the depressed rats; it reduced plasma surfactant protein, corticosterone, and corticotropin releasing hormone levels, increased neuropeptide Y and somatostatin levels, and upregulated interleukin-1β, -2, -6 protein expression in the hippocampal CA3 region. Somatostatin and interleukin-1β protein expression were negatively correlated with corticosterone level, and interleukin-1β protein expression was negatively correlated with corticotropin releasing hormone level. Results demonstrated that Jieyu No.1 decoction improved abnormal behaviors of depressed animals by regulating the function of the neuroimmunoendocrine system.