The human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS). A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression. Arsenic trioxide (As2O3), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane. This cardiotoxicity limits its clinical applications. Our aim was to develop cardioprotective agents to decrease As2O3-induced cardiotoxicity. We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 μM) increased the hERG current by promoting hERG channel activation. Long-term treatment with 1 μM matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As2O3. In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As2O3 in guinea pig ventricular myocytes. These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene. Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression.