Aim: The role of various host response mediators in pulpitis has been extensively documented as these components may operate as biomarkers that reflect the condition of pulp tissues. The expression of these biomarkers is further affected in the presence of different systemic diseases. This review aims to assess if a correlation exists in the expression of cytokines and endodontic infection in patients having various systemic diseases undergoing nonsurgical endodontic therapy. Materials and Methods: The review includes a complete manual search as well as electronic databases such as PubMed, Scopus, and EBSCOhost. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used to frame the review process. The critical appraisal checklist for quasi experimental studies developed by Joanna Briggs Institute was used to examine the risk of bias. For prospective clinical studies, eight criteria were used to assess the risk of bias. The studies included were clinical trials that estimated mRNA expression of cytokines from periapical interstitial fluid before and following disinfection of the root canals in patients suffering from various systemic diseases. Results: This review included a total of four papers from the initial 122 publications. When compared to normal controls, endodontic infection was associated with altered expression of these cytokines in patients presenting various systemic diseases. Conclusions: This information can subsequently be utilized to correctly distinguish between diseased and healthy pulp tissues. The interaction of cytokines in systemic diseases and their possible use in endodontics as a more precise and biologically based diagnostic tool can be planned.