High-Density Lipoprotein (HDL) had been known as a new potential therapy for atherosclerosis. HDL metabolism can be improved by targeting lipid metabolism through Reverse Cholesterol Transport (RCT) pathway. Apolipoprotein A-I mimetic peptides (ApoA-I MPs) are able to increase HDL metabolism. Thus, this systematic review aimed to examine the potential effect of ApoA-I MPs against atherosclerosis in mice model through the RCT mechanism. This systematic review was carried out by using previous in vivo studies during the last 10 years in four scientific databases (Pubmed, SCOPUS, ProQuest, and Science Direct) and based on the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) protocol. Decrease of atherosclerotic plaque was the primary outcome of this study and 16 articles were qualified to be included in this study. All of these articles had a low risk of bias based on the risk of bias analysis. Most in vivo studies (13 of 16) showed that ApoA-I MPs significantly reduced the formation of atherosclerotic plaque. Generally, ApoA-I MPs played an important role in regulation of HDL metabolism (HDL remodeling process, increased cholesterol efflux, and stimulated RCT pathway), and anti-inflammatory agent. The different efficacy of ApoA-I MPs to reduce atherosclerotic plaque may be influenced by the peptide sequence and administration route. In conclusion, ApoA-I MPs can reduce the formation of atherosclerotic plaque in mice by increasing cholesterol efflux via the RCT pathway. Further investigation is needed to support the development of ApoA-I MPs as a new therapy for atherosclerosis in human.