Andrographis paniculata
,
Syzygium cumini
, and
Caesalpinia sappan
are used as traditional medicines to treat diabetes mellitus. Therefore, this study aims to examine the antidiabetic effects and the acute toxicity of combined extract (1:1:1) of
A. paniculata
,
S. cumini
, and
C. sappan
(ASCE). The antidiabetic effect was tested using the rats model, induced by a high-fat diet and a double dose of streptozotocin injection of 35 mg/kg BW. Subsequently, diabetic rats in the experimental group were treated with 75 mg/kg BW and 150 mg/kg BW of ASCE, and those in the diabetic control group were treated with metformin 250 mg/kg BW. After seven days of treatment, fasting blood glucose (FBG), pancreatic β-cells numbers, and lipid profiles were used to analyze the antidiabetic effect. The results showed that the administration of 150 mg/kg BW ASCE significantly reduced FBG (
p
< 0.01), cholesterol levels (
p
< 0.05), LDL levels (
p
< 0.05), but not triglycerides, compared to diabetic control, this effect was comparable to metformin treatment. In addition, the pancreatic β-cells numbers were likely increased after ASCE treatment in a dose-dependent manner. The oral administration of a single dose of ASCE was safe up to 5000 mg/kg BW and did not result in any significant difference in body weight, relative organ weight, hematological and biochemical parameters compared with the control group. Therefore, it can be concluded that ASCE has a potential antidiabetic effect and can be safely developed as alternative medicine.