Context Cardiovascular disease is a major public health problem and represents a significant burden of disease globally. Lifestyle interventions have their limitations and an intervention that will effectively address cardiovascular risk factors to help reduce this growing burden of disease is required. Objective Carnosine and other histidine-containing dipeptides (HCDs) have exerted positive effects on cardiovascular risk factors and diseases in animal and human studies. The authors conducted a systematic review and meta-analysis examining the effects of HCDs on cardiovascular outcomes in line with the PRISMA guidelines. Data Sources The Medline, Medline in process, Embase, Cumulative Index of Nursing and Allied Health, and All EBM databases were searched from inception until January 25, 2019, for randomized controlled trials (RCTs) examining the effects of HCDs on cardiovascular outcomes, compared with placebo or controls. Data Extraction Basic characteristics of the study and populations, interventions, and study results were extracted. The grading of recommendations assessment, development, and evaluation approach was used to assess the quality of evidence for each outcome. Data Analysis A total of 21 studies were included. Of these, 18 were pooled for meta-analysis (n = 913). In low risk of bias studies, HCD-supplemented groups had lower total cholesterol (n = 6 RCTs; n = 401; weighted mean difference [WMD], −0.32 mmol/L [95%CI, −0.57 to −0.07], P = 0.01) and triglyceride levels (n = 6 RCTs; n = 401; WMD, −0.14 mmol/L [95%CI, −0.20 to −0.08], P < 0.001) compared with controls. In studies using carnosine alone, triglycerides levels were also lower in the intervention group vs controls (n = 5 RCTS; n = 309; P < 0.001). There were no significant differences in blood pressure, heart rate, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C) or the total cholesterol to HDL-C ratio between groups. Conclusions Carnosine and other HCDs may have a role in improving lipid profiles. Larger studies with sufficient follow-up are necessary to confirm these findings and explore the use of HCDs in the prevention of cardiovascular diseases. Systemic Review Registration PROSPERO registration no.: CRD42017075354