Endodontic treatment of permanent teeth (immature and mature) with propolis in healthy patients remains uncertain, with conflicting evidence. Therefore, this systematic review aims to evaluate the current literature on the safety and efficacy of propolis in endodontic procedures. An extensive literature search was performed using PubMed, Scopus, Web of Sciences, and Google Scholar. Only human randomized clinical trials (RCTs) that explored the clinical applications of propolis in endodontics were considered. Narrative synthesis was performed, and the risk of bias (RoB) for methodological quality assessment was performed with the Cochrane RoB-2 via the Robvis web-based application. Eight RCTs were selected, focusing on using propolis in vital pulps for direct pulp capping and non-vital pulps for root canal disinfection and filling materials. Propolis demonstrated promising effects, including controlling inflammation, promoting tissue healing, and disinfecting the root canal system. However, no significant differences were observed when comparing propolis to other materials used in pulp capping or intracanal medicaments. The RoB assessment revealed varied levels of risk, with two studies exhibiting a high risk, three having unclear risks, and three showing low risk. Moderate certainty of evidence was observed. Based on the current evidence, there is insufficient data to recommend propolis over other materials in the treatment of vital or non-vital pulps in permanent teeth. Propolis was not recommended as a definitive treatment due to the limited evidence and variability in the clinical outcomes across studies. However, future high-quality RCTs are essential for more definitive conclusions.