Background. Conventional antidiabetic drugs are linked with a number of contraindications and untoward effects. The root decoction of Solanum incanum L. has traditionally been used to treat diabetes. However, its safety and efficacy have not been scientifically authenticated yet. Hence, the study was conducted in mice to corroborate its antidiabetic potential and safety profile. Methods. Using normoglycemic, oral glucose-loaded, and streptozotocin-induced diabetic mice models, the hypoglycemic and antihyperglycemic activities of 80% methanolic root extract were investigated. On streptozotocin-induced diabetic mice, the effect of the test extract on diabetic lipid profile and body weight was also investigated. Further, the in vitro α-amylase inhibition activity was assessed. Results. The test extract was safe at a limit test dose of 2 g/kg. Dose-dependent α-amylase inhibition activity was seen with peak percentage inhibition of 75.95% at 700 μg/mL. In normoglycemic mice, the plant extract showed statistically significant hypoglycemic activity at 200 and 400 mg/kg (
P
<
0.001
) at 6 h and 4 and 6 h of treatment, respectively; in oral glucose-loaded mice, at both the test doses, the glucose level was also significantly dropped at 120 (
P
<
0.01
) and 60 and 120 min (
P
<
0.001
), respectively; whereas, in the third model, the test extract showed significant antihyperglycemic activity at 100 mg/kg (
P
<
0.05
) on the 14th day and at 200 (
P
<
0.01
) and 400 mg/kg (
P
<
0.001
) on the 7th and 14th day of treatment. Similarly, following repeated administration of the test extract at 200 and 400 mg/kg, the body weight was significantly improved on the 14th day (
P
<
0.05
) and on the 7th and 14th day (
P
<
0.01
), respectively, while diabetic dyslipidemia after 14 days (
P
<
0.05
). Conclusion. The study revealed that the test extract showed promising antihyperglycemic and antihyperlipidemic activity. Thus, the findings back up its use in Ethiopian remedies for diabetes.