Docetaxel (Doc) is the gold standard of care for castration-resistant prostate cancer (CRPC) patients, although the therapeutic effects are modest. Fuzheng Yiliu decoction (FZYL) comprises multiple herbs, and has been used for >10 years to treat various cancers, including hepatocellular tumors, malignant gastrointestinal tumors, and prostate cancer. In the study reported, we evaluated the anticancer effects of FZYL and of a combination of Doc and FZYL in CRPC tumor-bearing mice, and explored the underlying mechanisms. PC-3 tumor-bearing mice were treated with FZYL, Doc, Doc + FZYL or vehicle solution. Tumor volume was monitored, and tumor weight, proliferation and apoptosis of tumor tissues were measured. Deep sequencing was used to profile the miRNA expression patterns in tumor tissues. Our results suggested that FZYL alone could depress tumor growth, and the combination of Doc and FZYL treatment exhibited enhanced anticancer effects. Doc + FZYL regulated the expression of 10 miRNAs: miR-34b-5p, miR-674-3p, miR-140-3p, miR-342-3p, miR-214-3p, miR-149-5p, miR-378c, miR-29b-3p, miR-218-5p, and miR-378a-3p, involving in the PI3K-Akt pathway in the treatment of CRPC.