Background: Echeveria subrigida extracts have biological activities of human health importance. However, the in vivo effects on glucose levels and chronic toxicity are unknown. Objectives: To analyse the in vivo hypoglycemic and antihyperglycemic effects (50, 100, and 200 mg/kg b.w.) and chronic toxicity (1000 mg/kg b.w. for 270 days) of the hydroalcoholic extract of E. subrigida (HE-Es) in BALB/c mice. Materials and Methods: The HE-Es was analysed by HPLC. Glucose levels were measured to establish the effects on glycemia. Different parameters were registered in the toxicity assay: e.g., feed consumption, appearance/behaviour, biochemical and haematological parameters and liver and kidney histologies. Results: Quercetin-3-O-β-glucoside and isorhamnetin-3-O-β-glucoside were the main flavonoids in the HE-Es. Glycemia was reduced by the HE-Es (200 mg/kg b.w., 49.1%) and glibenclamide (10 mg/kg b.w., 52%) treatments. Comparing the antihyperglycemic activities, similar reductions were found between HE-Es (100 mg/kg b.w., 29.32%; 200 mg/kg, 28.99%) and acarbose (10 mg/kg b.w., 19.87%) treatments. On the other hand, the HE-Es was innocuous in mice (LD 50 > 1000 mg/kg b.w.), and the results suggested that HE-Es had adaptogenic, and immunostimulant activities. The hepatic and renal histologies were normal; however, male mice showed level zero steatosis that disappeared in the HE-Es satellite after treatment withdrawal. Conclusion: This study reports for the first time the in vivo effects on blood glucose levels of HE-Es and chronic toxicity of a Crassulaceae plant, supporting the antidiabetic potential and safety of HE-Es. Future studies must corroborate the effects of HE-Es in humans, allowing its use in high-value formulations.