Cancer related inflammation (CRI) is now recognized as the seventh hallmark in the pathogenesis of many types of malignancies. Paeonol, a natural phenolic component isolated from the root bark of Paeonia moutan, has significant anti-inflammatory activity. Recently, accumulating body of research has revealed potent anti-tumor effects mediated by paeonol. However, little is known about its anticancer mechanism on the basis of CRI. In this study, we observed that paeonol exerted direct anticancer activity through inhibition of cell proliferation, induction of apoptosis, and evident anti-inflammatory effects by reducing proinflammatory cytokines secretion (TNF-α, IL-1β, IL-6, and TGF-β) in the conditioned medium of B16F10 mouse melanoma cells. Interestingly, we found that paeonol significantly reversed motility phenotypes in TNF-α- or IL-6-induced B16F10 singe cell and collective migration and invasion in vitro, which were related to affecting epithelial-to-mesenchymal transition (EMT) makers and MMPs expression. In particular, paeonol disrupted both TNF-α-activated NF-κB and IL-6-activated STAT3 signaling pathways in B16F10 cells. EMSA and luciferase assays showed that paeonol abrogated NF-κB binding and NF-κB-driven promoter activity in the presence of TNF-α. Finally, we showed that paeonol attenuated B16F10 spontaneous lung metastases in C57/BL6J mice with down-regulated levels of serum proinflammatory cytokines. Therefore, paeonol possessed antitumor activity in melanoma cells and mice model by interruption of the aggressive feedback through proinflammatory cytokines mediated NF-κB and STAT3 signaling activation. These findings provide a novel treatment strategy that paeonol might be a promising versatile adjuvant therapy for cancer related inflammation.