Background New pharmacological therapies for the treatment of cardiovascular disease (CVD) have emerged in recent years. The high rates of CVD and the need for long-term treatment to decrease risk factors makes cost-effectiveness crucial for their successful long-term implementation. Objective This study assessed cost-effectiveness studies of novel pharmacological treatments (ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, omega-3 polyunsaturated fatty acids [n-3 PUFAs], and the cardiovascular polypill) compared with standard care for the secondary prevention of CVD. Methods We searched seven databases and the reference list of selected literature reviews for eligible cost-effective analyses (CEA) published between January 2009 and January 2020 that evaluated the above novel treatments versus standard care. Two independent reviewers performed the screening and evaluation in accordance with the Consolidated Health Economic Evaluation Reporting Standards statement. Cost results were adapted to 2018 US dollars (US$) to facilitate comparisons between studies. Consideration of cost-effectiveness was based on the original study criteria. Results Thirty-two studies were included in this review, most of them adopting a healthcare perspective. Studies evaluating ezetimibe, PCSK9 inhibitors and n-3 PUFAs assessed their addition to standard care compared with standard care alone, while studies analysing the polypill evaluated the replacement of multiple monotherapies for a fixed-dose combination. Ten studies reported on ezetimibe, fifteen evaluated PCSK9 inhibitors, five focused on n-3 PUFAs and seven on the polypill. From a healthcare perspective, ezetimibe was cost effective in 62.5% of the studies (incremental cost-effectiveness ratios [ICERs] ranged from US$27,195 to US$204,140), n-3 PUFAs in 60% (ICERs from US$57,128 to US$139,082) and the cardiovascular polypill in 100% (ICERs from dominant to US$30,731) compared with standard care. Conversely, only 10% of the studies considered PCSK9 inhibitors cost effective compared with standard care from a healthcare perspective (ICERs ranged from US$231,119 to US$1,223,831). Additionally, ezetimibe was cost effective in 50% of the studies, PCSK9 inhibitors in 33% and the polypill in 50% of the studies adopting a societal perspective. The key model-related parameters predicting cost-effectiveness included drug cost, time horizon, and the baseline risk of cardiovascular events. Conclusions Based on current pricing and willingness-to-pay thresholds, most CEA studies considered ezetimibe, n-3 PUFAs and the polypill to be cost effective compared with standard care but not PCSK9 inhibitors for secondary prevention of CVD.