Autophagy is a tightly regulated catabolic process that is essential for cellular homeostasis, stress adaptation, and metabolic balance. Its dysregulation has been implicated in a wide range of diseases, including cancer, neurodegenerative disorders, metabolic syndromes, muscular diseases, and infections. Recent studies have revealed the central roles of transcription factors, including TFEB, FOXO family members, p53, and NF-κB, in orchestrating autophagy through their direct regulation of lysosome-related genes. These factors often interact with epigenetic regulators such as histone acetyltransferases, deacetylases, and methyltransferases, which fine-tune chromatin accessibility and transcriptional output. Dysregulation of these pathways leads to aberrant autophagy and contributes to pathogenesis. Emerging therapeutic strategies targeting these transcriptional and epigenetic regulators have shown promise in preclinical and clinical settings, although challenges remain owing to the context-specific roles of autophagy in promoting either cell survival or cell death or contributing to protein aggregation and metabolic imbalance, depending on the disease. Clinical trials with autophagy modulators, including mTOR inhibitors, HDAC inhibitors, SIRT1 activators, and TFEB agonists, have yielded variable outcomes, emphasizing the need for precision medicine approaches. Advances in nanomedicine and biomaterials provide innovative delivery platforms that increase the specificity, bioavailability, and tissue targeting ability of autophagy-targeting agents. This review provides a comprehensive and detailed synthesis of how transcriptional and epigenetic regulators control autophagy across physiological and pathological contexts. In addition, we discuss therapeutic efforts, challenges in clinical translation, and future directions, including biomarker discovery, combinatorial treatment strategies, and targeted delivery systems, to enable more effective modulation of autophagy in disease.