The “One Health approach” has evidenced the significant impact of xenobiotic exposure to health, and humans are a relevant target for their toxic effects. Bisphenol A (BPA) exerts a ubiquitous exposure source in all ecosystems. Given its endocrine-disrupting and harmful consequences on health, several countries have enforced new regulations to reduce exposure to BPA. Cardiovascular diseases (CVDs) are complex conditions that lead to higher mortality worldwide, where family history, lifestyle, and environmental factors, like BPA exposure, have a remarkable contribution. This chemical compound is the most widely used in plastic and epoxy resin manufacturing and has been associated with effects on human health. Therefore, new-generation bisphenols (NGBs) are replacing BPA use, arguing that they do not harm health. Nonetheless, the knowledge about whether NGBs are secure options is scanty. Although BPA’s effects on several organs and systems have been documented, the role of BPA and NGBs in CVDs has yet to be explored. This review’s goals are focused on the processes of endothelial activation (EA)–endothelial dysfunction (ED), a cornerstone of CVDs development, bisphenols’ (BPs) effects on these processes through oxidant and antioxidant system alteration, and the potential benefits of antioxidant compounds to mitigate BPs’ effects on the CVS. Despite the scarce evidence on pro-oxidant effects associated with NGBs, our review demonstrated a comparable harmful effect on BPA. The results from the present review suggest that the biological mechanisms proposed by BPs to explain their cardiotoxic effects are the oxidant stress ↔ inflammatory response ↔ EA ↔ ED → atherosclerotic plate → coagulation promotion. Other effects contributing to CVD development include altered lipid metabolism, ionic channels, and the activation of different intracellular pathways, which contribute to ED perpetuation in a concerted manner.