Prostate cancer (PCa) is a leading adult malignant tumor. Recent research has shown that speckle-type BTB/POZ protein (SPOP) mutant is the top frequently mutated gene in PCa, which makes it an important biomarker. In this paper, we aimed at identifying critical genes and pathways related to SPOP mutation in PCa. Recent The Cancer Genome Atlas data showed that 12% of patients with PCa were SPOP mutant. There were 1,570 differentially expressed genes, and online enrichment analysis showed that these genes were mainly enriched in metabolism, pathways in cancer and reactive oxygen species. INS, GNG13, IL6, HTR5A, SAA1, PPY, CXCR5, CXCL13, CD19 and CCL20 were identified as hub genes. The lower SPOP expression level was associated with poor prognosis. In all, our findings showed that various pathways and genes could play critical roles in SPOP mutation in PCa, providing potential options for individualized treatment.