Introduction: Ventricular arrhythmia is commonly provoked by acute cardiac ischemia through sympathetic exaggeration and is often resistant to anti-arrhythmic therapies. Thoracic epidural anesthesia has been reported to terminate fatal ventricular arrhythmia; however, its underlying mechanism is unknown. Methods: Rats were randomly divided into four groups: sham, sham plus bupivacaine, ischemia/reperfusion (IR), and IR plus bupivacaine groups. Bupivacaine (1 mg/mL, 0.05 mL/100 g body weight) was injected intrathecally into the L5–L6 intervertebral space prior to establishing a myocardial IR rat model. Thereafter, cardiac arrhythmia, cardiac function, myocardial injury, and electrical activities of the heart and spinal cord were evaluated. Results: Intrathecal bupivacaine inhibited spinal neural activity, improved heart rate variability, reduced ventricular arrhythmia score, and ameliorated cardiac dysfunction in IR rats. Furthermore, intrathecal bupivacaine attenuated cardiac injury and myocardial apoptosis and regulated cardiomyocyte autophagy and connexin-43 distribution during myocardial IR. Conclusion: Our results indicate that intrathecal bupivacaine blunts spinal neural activity to prevent cardiac arrhythmia and dysfunction induced by IR and that this anti-arrhythmic activity may be associated with regulation of autonomic balance, myocardial apoptosis and autophagy, and cardiac gap junction function.