Background/Objectives: Fouquieria splendens Engelm. is a medicinal plant traditionally used in North America for treating metabolic disorders; however, its antihyperglycemic properties and safety profiles remain poorly studied. We investigated the phytochemical composition, oral acute toxicity, mutagenicity, and antihyperglycemic activity of the foliar ethanolic extract of F. splendens (EFS). Methods: Phytochemical analysis was performed using ultra-performance liquid chromatography–mass spectrometry. Acute toxicity and mutagenicity were evaluated following the OECD guidelines. Antihyperglycemic activity was assessed in streptozotocin-induced diabetic rats treated with EFS (200 mg/kg) alone or in combination with metformin for 30 days. Results: Eleven phenolic compounds were identified in the EFS, including ellagic acid, morin, apigenin, and luteolin 7-Oglucoside. EFS was non-mutagenic and had an LD₅₀ of >2000 mg/kg. This treatment significantly reduced blood glucose levels and enhanced the effect of metformin in diabetic rats. Histopathological analysis showed preserved morphology in the pancreatic, hepatic, and renal tissues of the treated animals. Conclusions: EFS exhibited significant antihyperglycemic activity and a favorable safety profile, supporting its potential as a complementary phytotherapeutic agent for diabetes management. These results highlight the pharmacological value of F. splendens and promote the exploration of native plants as adjuncts for chronic disease therapy.