Short QT syndrome (SQTS), a new genetic channelopathy, is characterized by the abbreviated QT interval on ECG and abbreviated effective refractory period (ERP) of ventricles and atrium, associated with syncope and a higher risk of sudden cardiac death (SCD) due to malignant arrhythmias. To our knowledge, pro-arrhythmogenic effects of SQTS have been extensively characterized, but less is known about the pharmacology of SQTS. Therefore, we built a drug-blocking model to predict the effects of propafenone on SQTS. The biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate the drug-blocking model and the potassium current formulations including SQT1, SQT2, and SQT3. The modified ventricular cell model was then integrated into one-dimensional strand tissue with transmural heterogeneities. Effects of propafenone on ventricular activities and pseudo-ECGs were simulated and quantified. The results showed that propafenone prolonged the action potential duration (APD) and QT interval in SQT1, and decreased the T-wave amplitude. However, it shortened the APD and QT interval in SQT2 and SQT3. Propafenone in SQT1 decreased the maximal transmural voltage heterogeneity and transmural heterogeneity of APD across the strand tissue, which contributed to the decreased T-wave amplitude. These findings provide new evidence of anti-arrhythmic effects of propafenone on SQT1 and pro-arrhythmic effects on SQT2 and SQT3.