Clinical use of antibiotics prophylaxis (AP) for preventing infective endocarditis (IE) after invasive dental procedures is controversial. Expert consensus guidelines are inconsistent, either restricting its use to high-risk individuals or advising its use again. To determine whether there is a genuine need for AP to prevent IE in high-risk patients undergoing invasive dental procedures. Online search was performed on PubMed, Science Direct, British Dental Journal and Cochrane Register of Controlled Trials. The methodological quality of each study was assessed using the Cochrane Handbook for Systematic Reviews of Interventions. Seventeen (17) clinical trials were included in the final analysis recruiting 2,410 patients (AP = 1,366; placebo = 1,044). Bacteraemia was detected in 302 AP patients (22.1%) and 362 placebo patients (34.7%). AP reduced the risk of bacteraemia by 49% (risk ratio: 0.51; 95% CI; 0.45 to 0.58; P = 0.0001). Although using AP for IE may be pragmatic and justified for high-risk patients undergoing invasive dental procedures, the evidence is inconclusive because post-procedural bacteraemia may not be a good surrogate marker for IE. Moreover, trials investigating the direct association between AP and IE are lacking due to low disease prevalence and high-cost challenges.