Tumor drug resistance is the primary cause of treatment failure in cancer therapy, with its underlying mechanisms closely tied to cancer cells" adaptive responses to environmental stress during treatment. As the central hub of cellular energy metabolism and stress responses, mitochondria drive drug resistance by enhancing cancer cell metabolic plasticity and survival. This is mediated through mechanisms such as activation of oxidative phosphorylation, regulation of reactive oxygen species (ROS) homeostasis, aberrant metabolite accumulation, and alterations in mitochondrial dynamics, positioning mitochondria as pivotal contributors to therapeutic resistance. Targeting mitochondrial metabolism has demonstrated significant potential to reverse drug resistance in contemporary oncology. This article reviews the adaptive mitochondrial changes in tumor cells under therapeutic stress, explores the multifaceted mechanisms by which mitochondrial metabolism induces resistance across various treatment modalities, and summarizes ongoing research on mitochondria-targeted metabolic therapies. Therefore, future mitochondria-targeted interventions are poised to transition from foundational mechanistic studies to clinical applications, offering novel perspectives for advancing personalized cancer treatment.