Objective To observe the effects of nonsteroidal anti-inflammatory drug, naproxen, on the cardiac electrophysiological characteristics and explore its potential adverse effects and mechanisms. Methods Langendorff isolated heart perfusion method and intracellular microelectrode technique were employed to observe the effects of naproxen on the fast and slow response action potentials of cardiac muscle cell, myocardial contractility of isolated heart, and electrocardiograms of isolated heart and whole heart. Results Naproxen shortened the duration of action potential (APD50 and APD90) and effective refractory period of ventricular papillary muscle of guinea pigs in a concentration dependant way, slowed down the rise speed of phase zero (Vmax), and decreased the phase 4 automatic depolarization rate (SDVP4) of slow response action potential, self exciting frequency, and rising amplitude of phase 0 action potential of rabbit sinoatrial node. In isolated heartelectrocardiogram tests, naproxen reduced the sinus heart rate, while prolonged the RR interval and the duration of QRS complex waves. Naproxen of 10-5 mol/L caused serious atrioventricular block and weakened the myocardial contraction force in a dose dependant way. The heart rate variability analysis showed that naproxen significantly increased both values at low frequency  (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.4 Hz), but the value of LF/HF decreased remarkably in a concentration dependant way. Conclusion Naproxen may affect the cardiac function by inhibiting Na⁺ and Ca²⁺ channels and promoting K⁺ channel or regulating the autonomic nervous system, especially the parasympathetic system.