Hydrocotyle bonariensis is one of the medicinal plants used in traditional medicine for the management of hypertension in Africa, Asia, and Latin America. However, the real impact of the traditional use of this plant on arterial hypertension has not yet been the subject of conclusive scientific information in the literature. This study aimed essentially to evaluate the potential cardiomodulatory effect of the hydroethanolic extract of Hydrocotyle bonariensis. In other to do so, the hydroethanolic extract of H. bonariensis was studied in vivo on the Wistar rat ECG and then in vitro on the isolated perfused Wistar rat heart using the Langendorff system. The extract was also tested on isolated guinea pig atria kept alive in the organ-specific vessel under physiological conditions similar to those of a living organism. At the cellular level, the effects of the extract were evaluated on the human cardiac sodium current INav1.5 and on the human cardiac pacemaker current If. We noted that the extract caused a decrease in P wave and T wave amplitudes and heart rate and an increase in the duration of the RR interval on the in vivo rat ECG. On the isolated perfused Langendorff heart as well as on the isolated atria, a decrease in the RR interval and in the heart rate was noted. The extract had no effect on human cardiac sodium current, but it did reduce human cardiac pacemaker current. In conclusion, the present study demonstrated that Hydrocotyle bonariensis, a medicinal plant traditionally used to prevent and treat hypertension, has an overall cardiomoderating effect. This effect would contribute to the reduction of blood pressure.