Blood glucose homeostasis and insulin signaling pathway regulation take a vital role in the management of diabetes mellitus. Our present was designed to explore the mechanism of the blood homeostasis, regulation of oxidative stress and insulin signaling pathway by guava leaf extract (GLE). Diabetes mellitus was induced in male albino Wistar by streptozotocin (STZ) (Single dose-40 mg/kg b.w.). As an extension STZ rats received GLE (GLE; 200 mg/kg b.w). At the end of the study the lipid peroxidation products, antioxidants, insulin signaling genes were analyzed. Treatment with GLE resulted in decreased plasma and skeletal muscle lipid peroxidation markers, increased antioxidants, and improved insulin signaling genes. GLE treatment helps to maintain blood homeostasis alleviates oxidative stress and regulates the insulin signaling genes in skeletal muscle. Overall the results suggest GLE treatment regulates blood glucose, inhibits oxidative stress, and importantly it regulates insulin signaling pathway genes in skeletal muscle. Further studies on the GLE role in other important pathways can add additional strength to the claim that GLE is a strong anti-diabetic candidate.