Mitochondrial ATP production is continually adjusted to energy demand through coordinated increases in oxidative phosphorylation and NADH production mediated by mitochondrial Ca²⁺([Ca²⁺]_m). Elevated cytosolic Na⁺ impairs [Ca²⁺]_m accumulation during rapid pacing of myocytes, resulting in a decrease in NADH/NAD⁺ redox potential. Here, we determined 1) if accentuating [Ca²⁺]_m accumulation prevents the impaired NADH response at high [Na⁺]_i; 2) if [Ca²⁺]_m handling and NADH/NAD⁺ balance during stimulation is impaired with heart failure (induced by aortic constriction); and 3) if inhibiting [Ca²⁺]_m efflux improves NADH/NAD⁺ balance in heart failure. [Ca²⁺]_m and NADH were recorded in cells at rest and during voltage clamp stimulation (4Hz) with either 5 or 15 mmol/L [Na⁺]_i. Fast [Ca²⁺]_m transients and a rise in diastolic [Ca²⁺]_m were observed during electric stimulation. [Ca²⁺]_m accumulation was [Na⁺]_i-dependent; less [Ca²⁺]_m accumulated in cells with 15 Na⁺ versus 5 mmol/L Na⁺ and NADH oxidation was evident at 15 mmol/L Na⁺, but not at 5 mmol/L Na⁺. Treatment with either the mitochondrial Na⁺/Ca²⁺ exchange inhibitor CGP-37157 (1 μmol/L) or raising cytosolic P_i (2 mmol/L) enhanced [Ca²⁺]_m accumulation and prevented the NADH oxidation at 15 mmol/L [Na⁺]_i. In heart failure myocytes, resting [Na⁺]_i increased from 5.2±1.4 to 16.8±3.1mmol/L and net NADH oxidation was observed during pacing, whereas NADH was well matched in controls. Treatment with CGP-37157 or lowering [Na⁺]_i prevented the impaired NADH response in heart failure. We conclude that high [Na⁺]_i (at levels observed in heart failure) has detrimental effects on mitochondrial bioenergetics, and this impairment can be prevented by inhibiting the mitochondrial Na⁺/Ca²⁺ exchanger.