<p>Type 2 diabetes (T2D), a growing global health concern, is often exacerbated by obesity and is linked to severe complications<!-- Query ID="Q1" Text="Please check if the affiliations are captured and presented correctly. Amend if necessary."-->. Serpins, a superfamily of serine protease inhibitors, that includes SerpinA3 in humans and its homolog SerpinA3k in mice. SerpinA3k regulates angiogenesis, reactive oxygen species (ROS) production, inflammation, and fibrosis particularly in the context of experimental ocular injury. Furthermore, we have previously demonstrated that urinary SerpinA3 serves as an early biomarker of kidney damage, including diabetic nephropathy; however, its functional role in renal damage, obesity, and T2D remains largely unexplored. This study explored the impact of SerpinA3k deficiency on obesity and T2D and its associated metabolic dysfunctions. Wild-type (WT, <i>n</i> = 27) and SerpinA3k knockout (KO <i>n</i> = 26) male mice were randomly assigned to three groups: standard chow diet (SD), high-fat diet (HFD) to induce obesity, and HFD combined with streptozotocin to induce T2D (D2). All the mice were followed and studied after 27 weeks. As expected, WT + D2 mice presented severe hyperglycemia, hyperinsulinemia, increased fat tissue, visceral adipocyte hypertrophy, and renal hyperfiltration. In sharp contrast, diabetic SerpinA3k-deficient mice were protected against these alterations, displaying improved glycemic control, greater pancreatic insulin content, reduced insulin resistance, and favorable adipocyte size remodeling characterized by a lower proportion of medium and large adipocytes. Additionally, these mice showed preserved lipolytic function, and attenuated renal hyperfiltration. Our findings indicate that targeting SerpinA3k mitigates hyperglycemia and insulin resistance, preserves adipose tissue functionality, and potentially prevents metabolic complications. These results highlight SerpinA3k as a promising therapeutic target for T2D.</p>