Background and Purpose: Xin Su Ning (XSN) is a multi-herbal anti-arrhythmic medicine with strong clinical evidence endorsing its safety, tolerability and efficacy. The medicine contains over 70 identified active components, and the mechanisms of many are yet to be fully understood. In silico modelling has identified several compounds likely to be of pharmacological significance, one of which is Liquiritigenin (LTG). Experimental approach: To investigate the LTG’s mechanism on cardiac ion channels and to assess the compound’s broader anti-arrhythmic contribution to XSN, whole cell patch clamp experiments were carried out on a CHO cell line stably transfected to express hERG K+ channels. Key Results: LTG weakly inhibited the peak conductance of the channel with unusual bisigmoidal kinetics. Performing channel activation and inactivation kinetics experiments showed that at very low concentrations, LTG bound to the open hERG channel and antagonised hERG activation without affecting inactivation. Only at very high concentrations was hERG inactivation potentiated and channel conductance completely inhibited. Conclusions and Implications: This study suggests LTG may bind to multiple hERG channel sites and modulate channel activity to give an anti-arrhythmic effect.