OBJECTIVE: To investigate the protective effects of Guilong prescription (, GL) on chronic prostatitis (CP) and unravel the underlying mechanisms of its pharmacological effects. METHODS: The composition of GL was determined RESULTS: In GL, a total of 48 compounds were identified, including 14 flavonoids, 14 alkaloids, 11 carboxylic acids, 4 lactones, 2 glycosides, 2 terpenoids and 1 aldehyde. Network pharmacological analysis suggested that the mechanism of GL may be related to PI3K-Akt signaling pathway and cytokine expression. After treatment with GL, inflammatory pathological changes in the prostate of rats were significantly improved, and blood perfusion of the prostate was significantly decreased. GL reduced the expression of IFN-γ, CXCL1, TNF-α, IL-1β, iNOS, ICAM-1, p38 MAPK, p-p38 MAPK, PI3K, p-PI3K, NF-κB, p-NF-κB, IκBα, p-IκBα, GSK-3β, p-GSK-3β, p-Akt in CP rats, and increased the expression of IL-4 and IL-10 in CP rats. CONCLUSION: The chemical compositions of GL were first identified. GL can improve pathological changes in the prostate and recover the prostate blood perfusion of CP rats. The possible mechanisms of GL on CP involve increasing the expression of anti-inflammatory cytokines IL-4 and IL-10, inhibiting pro-inflammatory cytokines TNF-α, IL-1β, and IFN-γ, and down regulating the expression of CXCL1, iNOS, and ICAM-1