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Annexin A5 (ANXA5) is a Ca²⁺-dependent phosphatidylserine (PS)-binding protein classically employed as an apoptosis biomarker. Accumulating evidence now positions ANXA5 as a multifunctional regulator of membrane homeostasis, immunometabolism, and cellular adaptation to metabolic stress across the spectrum of diabetes mellitus (DM). This review synthesizes current mechanistic and translational insights identifying ANXA5 as a candidate molecular determinant of diabetic pathophysiology. Its conserved α-helical architecture and dual-promoter transcriptional regulation enable reversible, high-affinity PS binding and assembly of a two-dimensional (2D) crystalline lattice that underpins its diverse biological functions. In the pancreas, ANXA5 has been shown to inhibit islet amyloid polypeptide (IAPP) aggregation and shields β-cell membranes from amyloid-induced injury; it has also been proposed to modulate mitochondrial Ca²⁺ homeostasis via VDAC1-associated pathways. In insulin-responsive peripheral tissues, ANXA5 has been hypothesized to modulate insulin signaling fidelity and facilitate glucose uptake through putative IRS-1 interactions and lipid raft stabilization, although direct in vivo validation remains outstanding. In the diabetic endothelium, hyperglycemia-induced dysfunction of acid sphingomyelinase impairs ANXA5-mediated membrane resealing, thereby precipitating Ca²⁺ overload, inflammasome activation, and a prothrombotic state. Experimental studies further suggest that ANXA5 may promote M2 macrophage polarization and suppress TGF-β/Smad2/3 signaling, indicating potential roles in immunomodulation and fibrosis attenuation. Importantly, distinct disease contexts shape ANXA5 biology: in T2D, glucolipotoxic stress and IAPP aggregation drive ANXA5-dependent protective responses, whereas in T1D, circulating anti-ANXA5 autoantibodies may neutralize membrane-protective functions and amplify vascular injury risk. Emerging translational applications include recombinant ANXA5 (NEXUS) and Diannexin, although prospective clinical validation remains limited. To facilitate interpretation of the literature, we introduce an evidence-grading framework that distinguishes diabetes-validated mechanisms from biologically supported, incompletely validated, and speculative pathways.