New strategies for the treatment of clear-cell renal cell carcinoma (ccRCC) are urgently needed. Recently, accumulating evidence has demonstrated that sinomenine hydrochloride (SH), extracted from the plant sinomenium acutum, has potent anti-cancer activity in multiple human malignant solid tumors. However, the underlying molecular mechanism by which SH treatment exerts its antagonizing tumorigenic effects has not been clearly elucidated. In this study, we showed that SH treatment exerted profound effects on cell growth in ccRCC in a dose- and time-dependent manner in vitro . Furthermore, treatment with SH significantly suppressed the migration, invasiveness and angiogenesis of ccRCC cells in vitro . Mechanistically, we revealed that SH treatment blocked epithelial–mesenchymal transition (EMT) through the downregulation of the expression of the transcription factors Snail1 and Twist in ccRCC cells. Additionally, the depletion of p-Smad2 and p-Smad3 was required for SH treatment to inhibit EMT effectively. Taken together, these findings indicate an anti-cancer role for SH in ccRCC cells and reveal a potential molecular mechanism by which Smad / EMT axis functions in ccRCC, as its hyperactivation has been associated with cell proliferation, migration, invasiveness and angiogenesis in this cancer type. These observations suggest that SH can act as an efficacious adjuvant chemotherapeutic candidate that targets the Smad/EMT axis in patients with ccRCC.