Ginseng botanicals are increasingly used as complementary or alternative medicines for a variety of cardiovascular diseases, yet little is known about their cellular actions in cardiac muscle. Electro-mechanical alternans (EMA) is a pro-arrhythmic cardiac abnormality that results from disturbances of intracellular Ca²⁺ homeostasis. This study sought to determine whether a purified ginsenoside extract of Ginseng, Re, exerts effects to suppress EMA and to gain insight into its mechanism of action. Alternans was induced by electrically pacing cardiomyocytes at room temperature. Re (≥10 nM) reversibly suppressed EMA recorded from cat ventricular and atrial myocytes, and Langendorff-perfused cat hearts. In cat ventricular myocytes, Re reversibly suppressed intracellular Ca²⁺ ([Ca²⁺]_i) transient alternans. Re exerted no significant effects on baseline action potential configuration or sarcolemmal L-type Ca²⁺ current (I_Ca,L), Na⁺ current or total K⁺ conductance. In human atrial myocytes, Re suppressed mechanical alternans and exerted no effect on I_Ca,L. In cat ventricular myocytes, Re increased [Ca²⁺]_i transient amplitude and decreased SR Ca²⁺ content, resulting in an increase in fractional SR Ca²⁺ release. In SR microsomes isolated from cat ventricle, Re had no effect on SR Ca²⁺ uptake. Re increased the open probability of ryanodine receptors (RyRs), i.e. SR Ca²⁺ release channels, isolated from cat ventricle and incorporated into planar lipid bilayers. We conclude that ginsenoside Re suppresses EMA in cat atrial and ventricular myocytes, cat ventricular muscle and human atrial myocytes. The effects of Re are not mediated via actions on sarcolemmal ion channels or action potential configuration. Re acts via a subcellular mechanism to enhance the opening of RyRs and thereby overcome impaired SR Ca²⁺ release underlying EMA.