Oxidative stress is a key factor of comorbidities in obesity. A Mexican genotype of the medicinal mushroom Ganoderma lucidum (Gl) contains bioactive compounds showing antioxidant, hypocholesterolemic, anti-inflammatory, anticancer, and prebiotic properties. We assessed the effect of standardized Gl-1 and Gl-2 extracts (1%) consumed by obese C57BL/6 mice fed with a high-fat and sugar diet (HFSD), on weight increase, serum parameters, liver lipid accumulation, and the expression of antioxidant genes (glutathione peroxidase 1, catalase [CAT], superoxide dismutase [SOD] 1, SOD2) and proteins (CAT, SOD2, nuclear factor erythroid 2-related factor 2) in the liver. Fifty-six male C57BL/6 mice were randomized into seven groups involving the control and treatments during 17 weeks, as well as using metformin (Met, 250 mg/kg/day) as a reference drug. Serum lipids and glucose levels decreased in mice groups consuming Gl extracts and metformin, in comparison with the HFSD group, as follows: total cholesterol (-11.8% to -35.7%), triglycerides (-8.3% to -24.8%), low-density lipoprotein cholesterol (-19.6% to -51.6%), and glucose (-3.1% to -25.7%). Gl-1 and Gl-2 extracts showed antioxidant properties and prevented lipid accumulation in the liver. The expression of antioxidant genes and proteins was significantly higher (P < .001) in the mice groups consuming Gl extracts, as compared to the HFSD group. This evidence showed that Gl-1 and Gl-2 extracts prevented oxidative stress in the in vivo model of obesity induced by an HFSD.