Cancer drug resistance, encompassing both acquired and intrinsic chemoresistance, remains a significant challenge in the clinical management of tumors. While advancements in drug discovery and the development of various small molecules and anti-cancer compounds have improved patient responses to chemotherapy, the frequent and prolonged use of these drugs continues to pose a high risk of developing chemoresistance. Therefore, understanding the primary mechanisms underlying drug resistance is crucial. Wnt proteins, as secreted signaling molecules, play a pivotal role in transmitting signals from the cell surface to the nucleus. Aberrant expression of Wnt proteins has been observed in a variety of solid and hematological tumors, where they contribute to key processes such as proliferation, metastasis, stemness, and immune evasion, often acting in an oncogenic manner. Notably, the role of the Wnt signaling pathway in modulating chemotherapy response in human cancers has garnered significant attention. This review focuses on the involvement of Wnt signaling and its related molecular pathways in drug resistance, highlighting their associations with cancer hallmarks, stemness, and tumorigenesis linked to chemoresistance. Additionally, the overexpression of Wnt proteins has been shown to accelerate cancer drug resistance, with regulation mediated by non-coding RNAs. Elevated Wnt activity reduces cell death in cancers, particularly by affecting mechanisms like apoptosis, autophagy, and ferroptosis. Furthermore, pharmacological compounds and small molecules have demonstrated the potential to modulate Wnt signaling in cancer therapy. Given its impact, Wnt expression can also serve as a prognostic marker and a factor influencing survival outcomes in human cancers.