The dysregulation of transcriptional regulators is a critical feature in the progression of many malignancies. Hairy and enhancer of split homolog-1 (HES1), a member of the basic helix-loop-helix (bHLH) gene family, has emerged as a key player in tumorigenesis due to its regulatory roles in multiple cellular pathways. This review aims to systematically explore the relevance of HES1 in cancer development, emphasizing its activation through major signaling pathways such as Notch, Hedgehog, hypoxia, and Wnt, and its contribution to advanced tumor progression. Numerous studies have demonstrated that HES1 upregulates genes associated with stemness, proliferation, and metastasis, and its expression correlates with poor clinicopathological features, including enhanced tumor proliferation, self-renewal, migration, metastasis, and drug resistance. Furthermore, HES1 has been frequently identified as a downstream effector of critical oncogenic pathways, further consolidating its role in aggressive cancers. Based on current evidence, HES1 holds promise as both a prognostic biomarker and a potential therapeutic target in various lethal malignancies. A deeper understanding of HES1's molecular mechanisms could pave the way for the development of targeted interventions aimed at improving cancer outcomes.