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Type 2 diabetes mellitus (T2D) is a pervasive metabolic disorder driven by insulin resistance and progressive pancreatic β-cell failure, with a rapidly growing global prevalence. Its pathogenesis now extends beyond hyperglycemia to encompass intricate immunometabolic dysregulation, mitochondrial dysfunction, and organelle stress. However, a cohesive synthesis that integrates these disparate molecular mechanisms with contemporary therapeutic advancements remains missing. This review systematically investigates the immunometabolic axis, highlighting macrophage polarization and exosomes, as well as nanotube-mediated crosstalk with β-cells, and describes how mitochondrial dynamics disorder and impaired mitophagy become the core driving factors for β-cell failure. Lipotoxicity mediated by ceramides, diacylglycerols, and cholesterol imbalance is critically analyzed alongside proteotoxicity from islet amyloid polypeptide aggregation. We then chart the therapeutic evolution from glucocentric strategies to modern complication-centric paradigms, emphasizing SGLT2 inhibitors and GLP-1 receptor agonists that confer proven cardio-renal protection. Personalized treatment, multiomics integration, next-generation precision therapies, and holistic art-based interventions that promote sustainable lifestyle changes are further discussed. By connecting molecular insights to clinical application, this review provides a comprehensive resource for researchers and clinicians, aiming to advance T2D management and improve global patient outcomes.