Blockage of the human ether-à-go-go Related Gene (hERG) channel can result in life-threatening ventricular tachyarrhythmia. In an in vitro screening of herbal materials for hERG blockers using an automated two-microelectrode voltage clamp assay on Xenopus oocytes, an alkaloid fraction of Nelumbo nucifera Gaertn. (lotus) leaves induced ~50% of hERG current inhibition at 100 µg/mL. Chromatographic separation resulted in the isolation and identification of (-)-asimilobine, 1, nuciferine, 2, O-nornuciferine, 3, N-nornuciferine, 4, and liensinine, 5. In agreement with in silico predicted ligand-target interactions, 2, 3, and 4 revealed distinct in vitro hERG blockages measured in HEK293 cells with IC50s of 2.89, 7.91, and 9.75 μM, respectively. Since lotus leaf dietary weight loss supplements are becoming increasingly popular, the identified hERG blocking alkaloids were quantified in five commercially available products. Results showed pronounced differences in the content of hERG blocking alkaloids ranging up to 992 µg (2) in the daily recommended dose.