This study aimed to explore the effects of dexamethasone (DEX) and its combination with luteolin (LUT) on cardiac function during myocardial infarction (MI) in a mouse model. We evaluated whether the Keap1/Nrf2 pathway mediates the cardioprotective function of DEX both in vivo and in vitro. The MI mouse model was established by ligation of the left anterior descending coronary artery of wild-type (WT) and Nrf2 knockout mice. After recovery for 21 days, DEX or its combination with LUT was intraperitoneally administered at different doses to WT or Nrf2 knockout mice daily for 7 consecutive days. Mice treated with DEX at a low dose (50 μg/kg/day) showed better cardiac function, fewer cardiac lesions, and smaller infarct sizes compared with MI model mice. DEX (50 μg/kg/day) administration also significantly decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, increased the expression of antioxidative enzymes, and activated the Keap1/Nrf2/HO-1 pathway. However, in Nrf2 knockout mice, DEX treatment did not influence cardiac function, inflammation, the oxidative response, or Keap1/Nrf2/HO-1 activation. In the MI cell model, low concentrations of DEX attenuated the H₂O₂-induced decreases in cell viability and antioxidative enzyme levels and activated the Keap1/Nrf2/HO-1 pathway. Low doses of DEX exerted protective effects in MIR mice and MI cell models by improving cardiac function, eliminating ROS, inhibiting inflammatory responses, and activating antioxidative responses. The protective effects of DEX on myocardial tissues were mediated by the Keap1/Nrf2/HO-1 pathway.