Short QT syndrome (SQTS) is an inherited cardiac disease characterized by ventricular tachyarrhythmias leading to sudden cardiac death (SCD). SQT3 has been linked to the D172N or E299V gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K+ current (I K1 ). Until now, the only effective therapy is implantation of a defibrillator whereas clinical drug therapy is little known about it. Previous studies reported that anti-malarial drug chloroquine was an effective inhibitor of the mutant Kir2.1 channels. The effectiveness of chloroquine has demonstrated in SQT3 associated with D172N mutation, there is a reason to believe that it may be useful in the other mutations in SQT3, such as E299V mutation. Therefore, we aim to predict and compare the potential effects of drug chloroquine on SQT3 D172N and E299V mutations. In this study, the ten Tusscher model of ventricular cell was coupled with the SQT3 mutant I K1 patch clamp data. Our simulation data showed that chloroquine prolonged the ventricular cell action potential duration (APD) and QT interval under SQT3 condition, and demonstrated that chloroquine produced a therapeutic effect on different mutant SQT3. This study provides new evidence that chloroquine may be a potential generic drug for the treatment of SQTS.