Objective Mental health disorders (MHD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been widely studied. However, the underlying molecular mechanisms and, in particular, role of inflammatory cytokines and their associated signaling pathways has not been investigated in detail. To determine the potential role of cytokines and associated signaling pathways in CP/CPPS patients with MHD and in a CP/CPPS animal model. Methods Between July 2012 and August 2013, 810 CP/CPPS patients and 992 control subjects were enrolled in this case-control multicenter study, and serum cytokine levels were measured. Male Sprague-Dawley rats received multiple intracutaneous injections (neck, tail, and pelvic limbs) of an immuno-agent along with a pertussis-diphtheria-tetanus triple vaccine for autoimmune CP/CPPS development. After 45 and 60 days behavioral analysis was performed, and prostate and specific brain areas related to MHD were subjected to RT-qPCR and Western blot analysis of cytokine signaling pathways. Moreover, histological prostate examination, and detection of IL-1β levels in serum and cerebrospinal fluid (CSF) was performed. Results In CP/CPPS patients with significant MHD, elevated IL-1α, IL-1β, IL-4, IL-13, and TNF-α serum levels were observed. The above five cytokines in CP/CPPS rats were significantly elevated in prostate tissue (P