Hibiscus sabdariffa Linne (Malvaceae), an attractive plant believed to be native to Africa, is cultivated in Sudan as well as in Eastern Taiwan. Our former study has shown that extract from Hibiscus sabdariffa (HSE) is effective in combating atherosclerosis. However, how HSE attenuates atherosclerosis remains unclear. In this study, we found that HSE inhibited the serum-stimulated proliferation of smooth muscle cells (SMC) and triggered SMC to undergo apoptosis. The HSE-induced cell apoptosis was dose-dependent. We further used SB203580 (P38 inhibitor) to block cellular apoptosis. Our data showed possible potential in inhibiting SMC cell apoptosis via P38 mitogen-activating protein kinases (MAPK) pathway. HSE was found to induce P38 MAPK activation, thus, stimulating the phosphorylation of c-Jun. Therefore, HSE mediated cell death possibly via P38 MAPK signaling and then inhibited SMC proliferation. Consequently, HSE may be a useful natural component for preventing pathological changes of atherosclerosis.