Obesity remains a persistent threat to cardiovascular health. Exercise mitigates risk, but the therapeutic benefits of exercise are frequently beyond the capabilities of the aged, the very obese or those with prior injuries. Prior work from our laboratory has determined that maintenance of skeletal muscle mass through deletion of myostatin, a negative regulator of muscle growth, improves cardiovascular health in obese mice. This improvement occurs despite no change in physical activity, indicating that the metabolic state imbued by skeletal muscle is a major contributor to cardiovascular health. GAL3 (Lgals3) is a sugar-binding lectin and alternative RAGE upregulated by hyperglycemia, but its role in mediating endothelial dysfunction in the microvasculature is unknown. GAL3 was markedly increased in the plasma of overweight and obese patients, and dramatically increased in microvascular endothelial cells from diabetic patients. To investigate its role in regulating endothelial function in obesity, GAL3 knockout mice were intercrossed with obese db/db mice. Deletion of GAL3 did not alter body mass, adiposity, or plasma indices of glycemia and lipidemia, but levels of plasma reactive oxygen species were normalized. Obese mice exhibited profound endothelial dysfunction and hypertension, both of which were rescued by GAL3 deletion. Isolated microvascular endothelial cells from obese mice had increased expression of NOX1, which we have previously shown to contribute to increased oxidative stress and endothelial dysfunction. NOX1 expression was normalized in microvascular endothelium from obese mice lacking GAL3. Due to infertility, generating compound genetic models on the db/db background is challenging. We hypothesized that delivery of the orexigen, AgRP to the brain of C57BL6 mice using a brain-specific AAV would elicit sustained hyperphagia, obesity, and microvascular dysfunction. Retro-orbital administration of AgRP-AAV.PHP.eB resulted in tightly restricted expression of AgRP in the brain and a significant hyperphagic response on a standard chow diet with obesity at 10 weeks post-injection, comparable to db/db mice. Endothelial cell-specific GAL3 knockout combined with our novel AAV-induced obesity model recapitulated whole-body knockout studies. The specific loss of endothelial cell GAL3 prevented obesity-induced NOX1 upregulation and subsequent microvascular function. In summary, GAL3 contributes to microvascular endothelial dysfunction in obese mice, likely through a NOX1-mediated mechanism. Improvement of metabolism by increasing muscle mass, with metformin or enhancing insulin signaling through PTP1B deletion decreased microvascular GAL3 and NOX1 expression levels and advances a GAL3-NOX1 signaling axis as a potential therapeutic target to ameliorate the cardiovascular consequences of obesity.