Background and Purpose: Chronic bacterial prostatitis (CBP) is an inflammatory disease caused by persistent bacterial infection and reflux into the urethra resulting in overactivation of the prostate immune system. Traditional chinese medicine (TCM) combined with antibiotics is commonly used in clinical treatment of CBP, and polygonum capitatum (Pc) combined with ciprofloxacin (CIP) is effective in clinical treatment of CBP. However, the limited clinical promotion of drug combinations persists due to a rudimentary understanding of their underlying mechanisms. This study aims to reveal the potential synergistic mechanism of Pc and CIP to ameliorate CBP. Experimental Approach: CBP was induced by bilateral prostate injections of E. coli and treated with Pc and CIP. The therapeutic effect was evaluated, and transcriptome data analyzed via Ingenuity Pathway Analysis (IPA) to uncover molecular mechanisms. Tissue-thermal proteome profiling (Tissue-TPP) identified potential targets, and molecular docking predicted interactions between active compounds and key proteins. Key Results: Our findings demonstrated that Pc combined with CIP significantly improved CBP rats. RNA-Seq combined with IPA analysis showed that Pc combined with CIP significantly inhibited cytokine storm signaling pathway in CBP rats, especially the NF-κB/IL-6/JAK2/STAT3 pathway.Tissue-TPP identified Pik3cb as a direct target, with molecular docking showing gallic acid (GA) from Pc binding to Pik3cb. Additionally, GA combined with CIP also significantly improved CBP. Conclusion and Implications: The results indicate that Pc combined with CIP can mitigate CBP by targeting Pik3cb to inhibit NF-κB/IL-6/JAK2/STAT3 signaling pathway, and GA is the key active component in Pc.