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Objective Chemoresistance is a major problem during hepatocellular carcinoma (HCC) treatment; thus, finding novel chemosensitizers and elucidating the underlying mechanisms that contribute to chemoresistance in HCC is critical. Methods Cell viability assays were used to detect the combined effects of ulinastatin (UTI) and 5-fluorouracil (5-FU) on the proliferation of HCC cells. RT-qPCR, western blot, sphere formation, and aldehyde dehydrogenase 1 (ALDH1) activity assays were used to examine UTI-mediated effects on HCC cell stemness and related mechanisms. Results We constructed 5-FU-resistant HCC cell lines and found that their stemness was higher than parental cells, as evidenced by increased sphere-formation ability, ALDH1 activity, and expression of stemness regulatory genes. While UTI had no effect on the viability of HCC cells, it significantly reduced the stemness of 5-FU-resistant HCC cells, which was determined by decreased sphere-formation capacity, ALDH1 activity, and expression of stemness-related genes. Furthermore, UTI attenuated 5-FU resistance in 5-FU-resistant HCC cells and enhanced the 5-FU sensitivity of parental cells. Mechanistic studies revealed that UTI suppressed the Wnt/β-catenin pathway, which was responsible for the activity of UTI on the stemness of HCC cells. Conclusions UTI enhanced the 5-FU sensitivity of HCC cells by attenuating their stemness via inhibiting Wnt/β-catenin signaling.