The systematic review utilised multiple electronic databases to gather relevant literature, including PubMed, Scopus, EMBASE, Web of Science, and Medline. The search was conducted focusing on clinical studies where Enterococcus strains were isolated to assess their antimicrobial resistance. The search strategy was designed based on the PICO model, targeting patients with secondary/persistent endodontic infections (SPEI) and evaluating the resistance profiles of Enterococci to systemic antibiotics. A total of 584 studies were initially identified through database searches. After removing duplicates, 517 studies were excluded based on title and abstract screening, leading to the final inclusion of 11 clinical trials that met the eligibility criteria. The studies were conducted in various countries, including Brazil, Lithuania, Poland, Germany, Sweden, the United States, and Japan. The focus was on permanent teeth with post-treatment apical periodontitis undergoing endodontic retreatment. Data extraction was performed independently by two reviewers, who compiled details such as authorship, year of publication, country of study, sample groups, bacterial strains tested, antibiotics used, and resistance outcomes. The risk of bias was assessed using the ROB-2 platform, and all studies were considered to have a low risk of bias, with occasional minor deficiencies noted. The analysis revealed fluctuating resistance profiles of Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium) to various antibiotics over time. E. faecalis isolated from teeth with SPEI showed intermediate resistance to 16 antibiotics. The most effective antibiotics identified were the combination of amoxicillin and clavulanate, followed by amoxicillin and benzylpenicillin. In patients with penicillin allergies, moxifloxacin and azithromycin were suggested as alternatives, albeit with caution due to their varying resistance levels. The antibiotics demonstrating the highest resistance patterns against E. faecalis included clindamycin, gentamicin, metronidazole, and rifampicin, which are contraindicated in SPEI cases. Ongoing monitoring of antibiotic resistance patterns is crucial for effective endodontic treatment protocols. The emergence of resistance among Enterococci, particularly E. faecalis, necessitates regular susceptibility testing to inform clinical decisions and improve treatment outcomes. The findings underscore the need for health professionals to stay informed about the evolving resistance landscape to ensure safe and effective therapeutic regimens in endodontics.