Sesamin, a major lignin isolated from sesame (Sesamum indicum) seeds and sesame oil, is known to possess antioxidant and anti-inflammatory properties. Several studies have revealed that oxidative stress and inflammation play a major role in a variety of cardiovascular diseases (CVDs). This comprehensive review summarizes the evidence on the effects of sesamin on CVD and its risk factors, principally due to its antioxidant properties. Specifically, this review highlights the mechanisms underlying the anti-hypertensive, anti-atherogenic, anti-thrombotic, anti-diabetic, and anti-obesity, lipolytic effects of sesamin both in vivo and in vitro, and identifies the signaling pathways targeted by sesamin and its metabolites. The data indicates that RAS/MAPK, PI3K/AKT, ERK1/2, p38, p53, IL-6, TNFα, and NF-κB signaling networks are all involved in moderating the various effects of sesamin on CVD and its risk factors. In conclusion, the experimental evidence suggesting that sesamin can reduce CVD risk is convincing. Thus, sesamin can be potentially useful as an adjuvant therapeutic agent to combat CVD and its multitude of risk factors.