Diabetes mellitus (DM) is a common chronic disease. Recently, Leiurus quinquestratus venom (LQV) showed anti-diabetic effect against type-2 DM (T2-DM). This study aimed to optimize the therapeutic dose LQV in T2-DM rats. Forty-eight male rats were divided into eight groups (n=6) as follows; group 1 (Gp1) was served as a control. From Gp2 to Gp8, rats were fed in high fat diets (HFD), and then injected with a single dose of streptozotocin (30 mg/kg b.wt). Then, Gp2 was left as untreated T2-DM, while groups from Gp3 to Gp8 were treated with metformin (Met) (150 mg/kg b.wt), or with different doses of LQV (1/10 to 1/320 LD₅₀). Post a month of daily treatments; the body weight changes, biochemical parameters, and liver histopathological changes were recorded. The results showed that the glucose level had increased and accompanied with sever alterations in the liver architectures in T2-DM rats (Gp2). The treatment of T2-DM rats with Met, 1/10, 1/40, or 1/80 of LQV LD₅₀ decreased the glucose level, ameliorated the biochemical changes, and improved the liver architectures. However, the treatment of T2-DM rats with 1/160 or 1/320 LQV LD₅₀, did not show significant changes when compared to T2-DM rats. Collectively, the therapeutic dose of LQV that could be used to treat T2-DM rats ranged between 1/10 to 1/80 of LQV LD₅₀