Decalcification is defined as the process of reducing the minerals from the bone or any other kind of calcified tissue. Several root canals exhibit an excessive amount of mineral content and are found to be blocked. There are six major types of decalcifying agents such as EDTA, 5% trichloracetic acid, 5% nitric acid, 10% formic acid, formalin–nitric acid, and citric acid. The purpose of this systematic review was to determine the efficacy of EDTA and Citric acid in decalcifying the root canals. A systematic literature review from 2010 to 2022 was performed using databases such as PubMed, Medline, and ScienceDirect. The keywords used were “EDTA”, “Citric acid”, and “root canal decalcification”. PRISMA flowchart was used to describe the selection process of searched articles. The Cochrane risk of bias assessment method was used to assess the quality of the studies included. The majority of the included studies could not establish a clear comparison between EDTA and citric acid. More experimental studies need to be conducted to distinguish between these two materials.