Diabetes mellitus (DM) is a global public health issue causing systemic dysregulations, including severe liver complications. Type 2 diabetes (DM2) patients show elevated annexin A1 (AnxA1) levels, and in murine DM2 models, AnxA1 mitigates insulin resistance effects like hepatosteatosis. However, its role in DM1 is underexplored. This study investigates AnxA1's role in hepatocyte biology in a streptozotocin (STZ)-induced DM mouse model. Male C57BL/6 mice (WT and AnxA1-/-) were divided into control (CTR) and DM groups. DM was induced via STZ injection (65 mg/kg for 5 days). After 12 weeks, livers were collected for analysis. DM WT and AnxA1-/- mice showed weight loss and increased blood glucose, reflecting typical diabetic metabolic disruptions. Morphological evaluations revealed normal hepatocytes in WT CTR mice, while 70% of AnxA1-/- CTR mice showed cytoplasmic vacuolation. In DM groups, 50% of WT mice had vacuolated, damaged hepatocytes, increasing to 75% in AnxA1-/- DM mice, highlighting AnxA1's protective role. Hepatocyte glycogen levels were lower in DM mice, especially AnxA1-/-. Collagen deposition in the centrolobular veins and portal triads was higher in AnxA1-/- DM mice, indicating worsened fibrosis without AnxA1. Both DM WT and AnxA1-/- livers showed reduced fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGF-A), suggesting impaired regeneration. Inflammation varied between genotypes: WT DM mice had higher IL-10 and TNF-α, while AnxA1-/- DM mice showed increased monocyte chemoattractant protein-1 (MCP-1). Oxidative stress markers indicated increased reactive oxygen species (ROS) in AnxA1-/- DM hepatocytes, with differing trends in superoxide dismutase (SOD) and catalase (CAT) activities. Metabolites linked to the tyrosine, malate-aspartate, taurine, and hypotaurine pathways stood out in AnxA1 knockout mice, suggesting that these pathways are key in AnxA1-deficient mice. This highlights AnxA1's role in liver protection under diabetic conditions.