Background: Endodontic infections can have a significant impact on systemic health, leading to a complex interplay between the endodontic microbiota, host immune response, and systemic diseases. The burden of endodontic disease on healthcare systems globally is substantial, with millions of root canal treatments performed each year. The presence of apical periodontitis, a consequence of root canal infection, can result in progressive bone resorption, periapical lesions, and potentially systemic complications. The relationship between endodontic infections and systemic health conditions has garnered increasing attention due to the potential risks posed by untreated infections. Objective: This review aims to examine the relationship between endodontic infections and systemic health conditions, evaluate the effectiveness of different treatment options in improving systemic health outcomes, identify potential risk factors for the development of endodontic infections, and explore the mechanisms by which these infections may contribute to systemic inflammation and disease. The research also delves into the occurrence of bacteremia after root canal treatment and the modulation of systemic inflammatory markers in response to endodontic interventions. Conclusion: The findings of this research underscore the importance of understanding and addressing the systemic implications of endodontic infections for enhanced patient care and public health. The review highlights the intricate relationship between endodontic microbiota, host immune response, and systemic diseases, emphasizing the need for comprehensive management of endodontic infections to mitigate potential systemic complications. By shedding light on the impact of apical periodontitis on conditions such as cardiovascular diseases, diabetes mellitus, and adverse pregnancy outcomes, this study contributes to the growing body of evidence linking oral health to overall systemic well-being. Moreover, the research emphasizes the potential role of endodontic interventions in reducing systemic inflammation and improving patient outcomes, underscoring the significance of proactive measures in addressing endodontic infections for better systemic health.