Background: Intracellular Na⁺ accumulation during ischemia/reperfusion prompts cytosolic Ca²⁺ overload through reverse mode operation of the sarcolemmal Na⁺-Ca²⁺ exchanger. Cytosolic Ca²⁺ accumulation promotes mitochondrial Ca²⁺ (Ca²⁺_m) overload leading to mitochondrial injury. We investigated whether limiting sarcolemmal Na⁺ entry during resuscitation from VF attenuates Ca²⁺_m overload and lessens myocardial injury in a rat model of VF and closed-chest resuscitation. Methods: Hearts were harvested from 10 groups of 6 rats each representing baseline, 15 minutes of untreated VF, 15 minutes of VF with chest compression given for the last 5 minutes (VF/CC), and 60 minutes post-resuscitation (PR). VF/CC and PR included 4 groups each randomized to receive before chest compression the new NHE-1 inhibitor AVE4454B (1.0 mg/kg), the Na⁺ channel blocker lidocaine (5.0 mg/kg), their combination, or vehicle control. The left ventricle was processed for intracellular Na⁺ and Ca²⁺_m measurements. Results: Limiting sarcolemmal Na⁺ entry attenuated cytosolic Na⁺ increase during VF/CC and the PR phase and prevented Ca²⁺_m overload yielding levels that corresponded to 77% and 71% of control hearts at VF/CC and PR, without differences among specific Na⁺-limiting interventions. Limiting sarcolemmal Na⁺ entry attenuated reductions in left ventricular compliance during VF and prompted higher mean aortic pressure (110 ± 7 vs 95 ± 11 mmHg, p < 0.001) and higher cardiac work index (159 ± 34 vs 126 ± 29 g·m/min/kg, p < 0.05) with lesser increases in cardiac troponin I at 60 minutes PR. Conclusions: Na⁺-limiting interventions prevented excess Ca²⁺_m accumulation induced by ischemia and reperfusion and ameliorated myocardial injury.