Background: Trigonella foenum graecum (TG) Linn. (Methi) is widely used as a spice and known for its pharmacological properties. Objective: The current study was conducted to examine the efficacy of TG Linn., family: Fabaceae, against sodium arsenite-induced toxicity in mice. Materials and Methods: Sixty mice (Mus musculus) weighing about 25 g were randomized into six groups; each of ten mice: Group I served as untreated control; Group II received only sodium arsenite (100 ppm) in drinking water for 2 months. The Group III mice fed chronically with sodium arsenite for 2 months as in Group II and then fed a vehicle of 1:20 alcohol to distilled water (1:20) for 15 and 30 days, respectively; Group IV to VI mice were treated as in Group II and then fed with 50, 150, and 250 mg/kg of TG seed extract, once daily for 15 and 30 days. Results: The IC50of the seed extract was 66.78 μg/mL, and it reduced the activities of toxicity marker enzymes such as gamma glutamyl transferase, lactate dehydrogenase, lipid peroxidation, aspartate transaminase, alanine aminotransaminase, acid phosphatase, alkaline phosphatase, and pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 (P < 0.05 to P < 0.001) and elevated the activities of catalase, superoxide dismutase, and G6PD (P < 0.05 to P < 0.001), a similar trend was also noted with hematological variables. Further, the normal architecture of the kidney was retained in the TG-fed series than arsenic (As)-treated series. Urinary excretion of As was high in treated groups compared to controls (P < 0.05 to P < 0.001), and 150 mg/kg dose offered better protection than the other two doses. Conclusion: TG seed extract has revealed potent antioxidant properties and consequently can be used as a protective agent in As-induced toxicity.