The aim of the present study was to systematically assess existing evidence on the possible association between chronic endodontic infections and cardiovascular disease (CVD). An electronic database search was implemented until 2 October 2020. The main outcome was risk of CVD diagnosis. Risk of bias was assessed through the ROBINS-I tool, while random effects meta-analyses were conducted. The quality of the evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation. Twenty-one studies were eligible for inclusion, while 10 were included in the quantitative synthesis. Risk for CVD diagnosis in patients with chronic endodontic infection was 1.38 times those without infection (RR = 1.38; 95% CIs: 1.06, 1.80; p = 0.008). Risk of bias ranged from moderate to serious, while the quality of the evidence was graded as very low. Indications for an identified association between chronic endodontic infection and CVDs do exist; however, they are not grounded on high-quality evidence at present. Further research for an establishment of an association based on temporal sequence of the two entities and on unbiased well-conducted cohort studies would be highly valued.