Solanum incanum is a bushy perennial herb which is used for treatment of various ailments in East Africa including stomach pain, toothaches, ulcers, and cardiovascular diseases. However, there is scarcity of data on its safety, and its effect on the physiology of the cardiovascular system. Hence, this study envisaged evaluating the effect of methanol extract of the herb on myocardial action atherosclerotic tendency and safety. Myocardial activity assay involved determination of the heart rate and force of contraction using an isolated rabbit heart in an organ bath and kymograph, while antiatherosclerotic effects were assayed on blood obtained from white Wistar rats fed on high lipid diet where the levels of low‐density lipoproteins, high‐density lipoproteins and total cholesterol were determined. Assays of the toxic effects of the extract were carried out on Swiss albino mice while qualitative phytochemical analyses were carried out using one‐way Anova and Tukey as the post hoc test, a value of (p < 0.05) was taken as the limit of significance. The plant extracts exhibited an increase in the force of contraction of the heart and decrease in heart rate. It also caused significant (p < 0.05) reduction in serum low‐density lipoproteins and total cholesterol as well as elevation of HDL but no effect on hematological parameters. Phytochemical analyses showed the presence of alkaloids, glycosides, saponins flavonoids, terpenoids, steroids, and phenolics. Hence, the S. incanum root extract may contain compounds with antiatherosclerotic effects that are cardioprotective and therefore a potential source of novel remedies for the ailment.