The Notch signaling pathway plays a critical role in regulating cell fate, organ development, and tissue homeostasis across metazoans. It is highly conserved and involves transmembrane receptors and ligands with epidermal growth factor-like repeats. Accumulating evidence shows that the Notch pathway functions as both an oncogene and a tumor suppressor in various cancers. Dysregulation of this pathway promotes epithelial-mesenchymal transition, angiogenesis, and cancer progression. It also maintains stem-like properties in cancer cells, enhancing invasiveness. The Notch pathway is involved in cancer metabolic reprogramming and the tumor microenvironment, contributing to the balance between oncogenic and tumor suppressive effects. Additionally, it is implicated in conferring chemoresistance to tumor cells. Understanding these mechanisms is crucial for developing targeted therapies. This review discusses the role of the Notch pathway in cancer, its mechanisms, and clinical trials targeting Notch signaling for cancer therapy. The Notch pathway is involved in various cancers, including digestive system tumors, respiratory system tumors, hematological malignancies, urinary system tumors, reproductive system tumors, and nervous system neoplasms. It plays a significant role in the progression and prognosis of cancers such as colorectal cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, gastric cancer, pancreatic cancer, cholangiocarcinoma, non-small cell lung cancer, small cell lung cancer, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, prostate cancer, and renal cell carcinoma. The Notch pathway is involved in the regulation of cell proliferation, differentiation, and survival, and its dysregulation contributes to cancer progression. Targeting the Notch pathway is a promising approach for cancer therapy.The Notch signaling pathway plays a critical role in regulating cell fate, organ development, and tissue homeostasis across metazoans. It is highly conserved and involves transmembrane receptors and ligands with epidermal growth factor-like repeats. Accumulating evidence shows that the Notch pathway functions as both an oncogene and a tumor suppressor in various cancers. Dysregulation of this pathway promotes epithelial-mesenchymal transition, angiogenesis, and cancer progression. It also maintains stem-like properties in cancer cells, enhancing invasiveness. The Notch pathway is involved in cancer metabolic reprogramming and the tumor microenvironment, contributing to the balance between oncogenic and tumor suppressive effects. Additionally, it is implicated in conferring chemoresistance to tumor cells. Understanding these mechanisms is crucial for developing targeted therapies. This review discusses the role of the Notch pathway in cancer, its mechanisms, and clinical trials targeting Notch signaling for cancer therapy. The Notch pathway is involved in various cancers, including digestive system tumors, respiratory system tumors, hematological malignancies, urinary system tumors, reproductive system tumors, and nervous system neoplasms. It plays a significant role in the progression and prognosis of cancers such as colorectal cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, gastric cancer, pancreatic cancer, cholangiocarcinoma, non-small cell lung cancer, small cell lung cancer, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, prostate cancer, and renal cell carcinoma. The Notch pathway is involved in the regulation of cell proliferation, differentiation, and survival, and its dysregulation contributes to cancer progression. Targeting the Notch pathway is a promising approach for cancer therapy.