In the present study, we investigated the antiarrhythmic potential of the multichannel blocker CPUY11018 (CY18) in rat cardiac hypertrophy, induced using 7-day treatment with isoproterenol (ISO) (2.5 mg/kg day, s.c.). Arrhythmias were produced using a coronary ligation-reperfusion procedure. CY18 (3 and 10 mg/kg per day, i.p.) and valsartan (10 mg/kg per day, p.o.) were administrated on days 4–7 of ISO treatment. Heart weight index, hemodynamic parameters, electrocardiogram (ECG II) parameters, and arrhythmic scores were monitored and recorded. We examined the ability of CY18 to block the IKr channel under conditions of acidosis and excess reactive oxygen species production in CHO cells expressing the hERG. CY18 had strong antiarrhythmic effects, potentially due to multichannel inhibition. The protective role of CY18 against ISO-induced myocardial hypertrophy was further confirmed using ECG. Incidences of ventricular tachycardia and ventricular fibrillation, heart weight/body weight ratios, and arrhythmic scores were higher in the model group and were suppressed with CY18 treatment. Under simulated pathological conditions, the inhibitory effect of CY18 was impaired in cells treated with 30 μM H2O2, which was more effective than acidosis in attenuating CY18-induced inhibition of hERG channel activity.