Introduction: The N588K mutation to the human Ether-à-go-go-Related Gene (hERG) underlies short QT syndrome variant 1 (SQT1), which is associated with increased incidence of atrial fibrillation (AF). However, mechanisms and pharmacological management of AF in the context of SQT1 remain poorly understood. Methods: In this study, multi-scale computational modelling was used as a means of investigating mechanisms of human atrial arrhythmogenesis consequent to the N588K-hERG mutation, as well as pharmacotherapeutic effects of the class Ic drug propafenone. A Markov chain formulation of rapid delayed rectifier potassium current, IKr, describing wild type (WT), and N588K mutant hERG channel currents was incorporated into a contemporary model of the human atrial action potential (AP), which was subsequently integrated into a three-dimensional (3D) heterogeneous, anisotropic anatomical model of the human atria. Effects of multi-channel block by propafenone, including binding kinetics and altered potency of IKr/hERG block in SQT1 and state-dependent block of sodium channels, were simulated on single- and multi-cellular electrophysiology models. Results: At the single cell level, propafenone at clinically-relevant concentrations (0.2, 0.5, 0.8 μM) prolonged the AP duration, which was shortened by ~50 ms under heterozygous SQT1 (WT-N588K) conditions, in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In simulations of re-entrant excitation waves in the 3D anatomical model, propafenone partially reversed the SQT1-mediated increase in dominant frequency of re-entry (from ~4.2 Hz in the WT condition to ~5.0 Hz in the heterozygous SQT1 condition) and demonstrated some efficacy in pharmacological conversion of re-entry. Conclusion: Our findings show that propafenone has efficacious effects in reversing human AF associated with hERG-linked short QT syndrome. Further studies are warranted to establish whether propafenone represents a useful SQT1-specific pharmacotherapy for AF.