<p>Drug resistance is a formidable obstacle in the treatment of various cancers, significantly undermining the efficacy of therapeutic interventions and posing a substantial challenge to achieving optimal clinical outcomes. Emerging research has highlighted the critical role of the interplay between autophagy and cellular metabolism in driving drug resistance. Autophagy, a cellular recycling process, and metabolic reprogramming, which involves alterations in cellular metabolic pathways, collectively enable cancer cells to survive and proliferate despite therapeutic stress. This comprehensive review aims to elucidate the mechanisms by which autophagy and metabolism interact to confer drug resistance in cancer cells. We explore how autophagy supports cancer cell survival by recycling nutrients and maintaining cellular homeostasis under stress. Furthermore, we discuss about metabolic reprogramming, specifically enhanced glycolysis, oxidative phosphorylation, and fatty acid metabolism, and how these metabolic shifts contribute to the development of drug resistance.</p>