Quercetin (QUE), a natural flavone abundantly discovered in fruits, has gained attention for its potential health benefits due to its unique structure. In addition, epidemiological and clinical studies have shown promising antioxidant activity of QUE aiming to treat various diseases, including cancer. This article's purpose is to provide an overview of recent advances in the use of QUE for drug-resistant cancer therapies, focusing on its mechanisms, applications, and delivery systems. The review discusses the structure-function relationship of QUE and its role in mitigating various disorders. Furthermore, it highlights the impact of QUE on cancer and cancer stem cells, elucidating the signaling pathways at the cellular and molecular levels involved. Additionally, the review explores the mechanistic role of QUE in reversing drug resistance in different types of drug-resistant cancers. Moreover, it presents a comprehensive analysis of drug diverse delivery strategies employed for effective cancer treatment using QUE. Clinical studies investigating the safety and bioavailability of QUE are also discussed. Finally, the review concludes with future directions, emphasizing the use of cost-effective and efficient protein and peptide-based self-assembling hydrogels for targeted delivery of QUE.