N-Myc downstream regulated gene-1 (NDRG1) and the other three members of this family (NDRG2, 3, and 4) play various functional roles in the cellular stress response, differentiation, migration, and development. These proteins are involved in regulating key signaling proteins and pathways that are often dysregulated in cancer, such as EGFR, PI3K/AKT, c-Met, and the Wnt pathway. NDRG1 is the primary, well-examined member of the NDRG family and is generally characterized as a metastasis suppressor that inhibits the first step in metastasis, the epithelial-mesenchymal transition. While NDRG1 is well-studied, emerging evidence suggests NDRG2, NDRG3, and NDRG4 also play significant roles in modulating oncogenic signaling and cellular homeostasis. NDRG family members are regulated by multiple mechanisms, including transcriptional control by hypoxia-inducible factors, p53, and Myc, as well as post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Pharmacological targeting of the NDRG family is a therapeutic strategy against cancer. For instance, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have been extensively shown to upregulate NDRG1 expression, leading to metastasis suppression and inhibition of tumor growth in multiple cancer models. Similarly, targeting NDRG2 demonstrates its pro-apoptotic and anti-proliferative effects, particularly in glioblastoma and colorectal cancer. This review provides a comprehensive analysis of the structural features, regulatory mechanisms, and biological functions of the NDRG family and their roles in cancer and neurodegenerative diseases. Additionally, NDRG1-4 are explored as therapeutic targets in oncology, focusing on recent advances in anti-cancer agents that induce the expression of these proteins. Implications for future research and clinical applications are also discussed.