Background— Therapeutic strategies aimed at increasing hydrogen sulfide (H 2 S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear factor E2–related factor 2 (Nrf2) is a cellular target of H 2 S and facilitator of H 2 S-mediated cardioprotection after acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H 2 S therapy in the setting of heart failure. Methods and Results— Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type littermates were subjected to ischemic-induced heart failure. Wild-type mice treated with H 2 S in the form of sodium sulfide (Na 2 S) displayed enhanced Nrf2 signaling, improved left ventricular function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na 2 S therapy failed to provide protection against heart failure in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na 2 S increased the expression of proteasome subunits, resulting in an increased proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na 2 S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na 2 S failed to improve cardiac function when the proteasome was inhibited. Conclusions— These findings indicate that Na 2 S therapy enhances proteasomal activity and function during the development of heart failure in an Nrf2-dependent manner and that this enhancement leads to attenuation in cardiac dysfunction.