The WNT/β-catenin signaling pathway plays a critical role in tumorigenesis, metastasis, and drug resistance in various cancers. Aberrant activation of this pathway is common in many tumors, and its inhibition has shown potential in enhancing cancer treatment efficacy. This review summarizes the pharmacological targets and therapeutic potential of FDA-approved drugs and natural products in targeting the WNT/β-catenin pathway. It focuses on recent advances in WNT signaling inhibitors for improving chemotherapy, immunotherapy, gene therapy, and physical therapy. The review classifies these drugs based on their structure and physicochemical properties and discusses their mechanisms of action in inhibiting the WNT pathway. The review highlights the importance of targeting the WNT pathway in combination with various therapies to enhance cancer treatment outcomes. The WNT/β-catenin pathway is divided into canonical and non-canonical pathways. The canonical pathway is activated by regulating β-catenin accumulation in the cytoplasm. β-catenin is a core transcriptional co-activator of this pathway and is tightly controlled by the β-catenin destruction complex. In the absence of WNT ligands, β-catenin is phosphorylated and ubiquitylated, leading to its degradation. When WNT ligands are present, they bind to FZD receptors and co-receptors, leading to β-catenin accumulation and nuclear translocation, where it interacts with TCF/LEF to activate downstream target genes. In many cancers, mutations in WNT/β-catenin pathway components are frequent. For example, in colorectal cancer, APC mutations are common, and β-catenin mutations are also frequent in CRC without APC mutations. However, APC or β-catenin mutations in breast cancer are rare. The WNT receptor Frizzled 6 is frequently amplified and overexpressed in triple-negative breast cancer. The WNT pathway is also involved in hepatocellular carcinoma, where β-catenin activating mutations occur in 30–44% of cases. The WNT pathway is a fundamental growth control pathway, including embryonic development, cell cycle regulation, inflammation, and cancer. The activation of the WNT pathway can lead to drug resistance in cancer cells, and WNT inhibitors can sensitize cancer cells to chemotherapeutic agents. Several studies have shown that WNT inhibitors can enhance the efficacy of chemotherapy. However, the use of WNT inhibitors may lead to toxic effects in normal tissues, limiting their clinical application. Therefore, developing novel WNT inhibitors is urgently needed. FDA-approved drugs and natural products have shown potential as WNT inhibitors. For example, Niclosamide inhibits the WNT/β-catenin pathway by inducing LRP6 degradation and disrupting the AXIN-GSK3 interaction. Ivermectin inhibits the WNT/β-catenin pathway by reducing β-catenin phosphorylation and decreasing LRP6 phosphorylation.The WNT/β-catenin signaling pathway plays a critical role in tumorigenesis, metastasis, and drug resistance in various cancers. Aberrant activation of this pathway is common in many tumors, and its inhibition has shown potential in enhancing cancer treatment efficacy. This review summarizes the pharmacological targets and therapeutic potential of FDA-approved drugs and natural products in targeting the WNT/β-catenin pathway. It focuses on recent advances in WNT signaling inhibitors for improving chemotherapy, immunotherapy, gene therapy, and physical therapy. The review classifies these drugs based on their structure and physicochemical properties and discusses their mechanisms of action in inhibiting the WNT pathway. The review highlights the importance of targeting the WNT pathway in combination with various therapies to enhance cancer treatment outcomes. The WNT/β-catenin pathway is divided into canonical and non-canonical pathways. The canonical pathway is activated by regulating β-catenin accumulation in the cytoplasm. β-catenin is a core transcriptional co-activator of this pathway and is tightly controlled by the β-catenin destruction complex. In the absence of WNT ligands, β-catenin is phosphorylated and ubiquitylated, leading to its degradation. When WNT ligands are present, they bind to FZD receptors and co-receptors, leading to β-catenin accumulation and nuclear translocation, where it interacts with TCF/LEF to activate downstream target genes. In many cancers, mutations in WNT/β-catenin pathway components are frequent. For example, in colorectal cancer, APC mutations are common, and β-catenin mutations are also frequent in CRC without APC mutations. However, APC or β-catenin mutations in breast cancer are rare. The WNT receptor Frizzled 6 is frequently amplified and overexpressed in triple-negative breast cancer. The WNT pathway is also involved in hepatocellular carcinoma, where β-catenin activating mutations occur in 30–44% of cases. The WNT pathway is a fundamental growth control pathway, including embryonic development, cell cycle regulation, inflammation, and cancer. The activation of the WNT pathway can lead to drug resistance in cancer cells, and WNT inhibitors can sensitize cancer cells to chemotherapeutic agents. Several studies have shown that WNT inhibitors can enhance the efficacy of chemotherapy. However, the use of WNT inhibitors may lead to toxic effects in normal tissues, limiting their clinical application. Therefore, developing novel WNT inhibitors is urgently needed. FDA-approved drugs and natural products have shown potential as WNT inhibitors. For example, Niclosamide inhibits the WNT/β-catenin pathway by inducing LRP6 degradation and disrupting the AXIN-GSK3 interaction. Ivermectin inhibits the WNT/β-catenin pathway by reducing β-catenin phosphorylation and decreasing LRP6 phosphorylation.