Objective: The present study aims to investigate the effect of Huaier on oxaliplatin (OXA) resistance in HCT-8 colorectal cancer (CRC) cells. Methods: Oxaliplatin-resistant HCT-8/L CRC cells were used. The Cell Counting Kit-8, western blotting, quantitative real-time polymerase chain reaction, protein extraction kit, immunofluorescence and acridine orange staining assays were used in the study. The experiment results proved that Huaier has an influence on the Wnt/\beta-catenin signalling pathway, autophagy and drug resistance. The authors of the present study used chloroquine, an autophagy inhibitor and Wnt agonist 1 (a Wnt pathway agonist) to verify the present experiment. Results: The results showed that Huaier can regulate autophagy, inhibit the Wnt/\beta-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells. Conclusions: This study proved that Huaier can regulate autophagy, inhibit the Wnt/\beta-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells.