Docetaxel remains the standard treatment for castration-resistant prostate cancer by improving overall survival but having severe adverse toxicity. Inflammatory cytokines in the tumor microenvironment promote docetaxel resistance through activation of IKKα/β-NFκB pathways. To tackle such chemotherapy-elicited adverse effects, this study demonstrates the standardized Wedelia chinensis herbal extract effectively inhibited the production of tumor-promoting cytokines, therefore inhibiting angiogenesis, tumor growth, and metastasis. Transcriptomic analysis of tumors revealed that WCE modulates inflammatory tumor microenvironment by suppressing the expression of HIF1α, IKKα/β phosphorylation and the downstream cytokines/chemokines, e.g., IL6, CXCL1, and CXCL8, thus reduced tumor-elicited chemotaxis and infiltration of MDSCs, TAMs, and endothelial cells into the tumors. Furthermore, WCE suppresses the expansion and activity of MDSCs by downregulating STAT3 activity and also prevents the differentiation of macrophages toward tumor-promoting M2 phenotype. On the other hand, co-treatment of docetaxel with this botanical preparation caused significant enhancement of the docetaxel-mediated therapeutic efficacy, while prevented the drug resistance and toxicity.