Objective Major depression is an important clinical factor in ventricular arrhythmia. Patients diagnosed with major depression overexpress N-methyl-d-aspartate receptors (NMDARs). Previous studies found that chronic NMDAR activation increases susceptibility to ventricular arrhythmias. We aimed to explore the mechanisms by which NMDAR activation may increase susceptibility to ventricular arrhythmias. Methods Male rats were randomly assigned to either normal environments as control (CTL) group or 4weeks of chronic mild stress(CMS) to produce a major depression disorder (MDD) model group. After 4 weeks of CMS, depression-like behaviors were measured in both groups. Varying doses (1-100μM) of NMDA and 10μM NMDA antagonist (MK-801) were perfused through ventricular myocytes isolated from MDD rats to measure the L-type calcium current (I_Ca-L) and transient outward potassium current(I_to). Structural remodeling was assessed using serial histopathology including Masson's trichrome dye. Electrophysiological characteristics were evaluated using Langendorff perfusion. Results Depression-like behaviors were observed in MDD rats. MDD rats showed longer action potential durations (APD) at 90% repolarization and higher susceptibility to ventricular arrhythmias than CTL rats. MDD rats showed lower I_Ca-L and Ito current densities than CTL rats. Additionally, NMDA reduced both currents in a concentration-dependent manner, whereas no significant impact on the currents when perfused with MK-801. MDD rats exhibited significantly more fibrosis areas in heart tissue and reduced expression of Kv4.2, Kv4.3, and Cav1.2. Conclusions We observed that acute NMDAR activation led to down-regulation of potassium and L-type calcium currents in a rat model of depression, which may be the mechanism underlying ventricular arrhythmia promotion by depression.