BACKGROUND Malignant nonendodontic periapical lesions represent a rare diagnosis, in which few case have been reported about this condition. Due to the low occurrence and little exploration of this subject, serious errors of diagnosis are observed in the oral medicine services. In this sense, the purpose of the present review was to integrate the information on the record published on malignant lesions that mimic endodontic pathoses into a comprehensive analysis of their clinical, radiologic, and histopathologic features. METHODS An online search was made in March 2020 in the following databases: Pubmed, Web of Science, and Scopus. Eligibility criteria included publications having enough clinical, radiologic, and histopathologic information to confirm the diagnosis. Data were assessed descriptively. RESULTS Forty-nine publications from 16 countries comprising 60 cases were included. There is a nearly equal occurrence rate between males and females (male/female ratio is 49.15%/50.84%) with a mean age of 46.56 years. The lesions were more prevalent in the posterior mandibles (40.69%), and, radiographically, they were unilocular radiolucent. Histopathologic analysis showed metastasis (26.67%) as the most prevalent lesion followed by salivary gland malignant disease (25%). CONCLUSIONS The present systematic review revealed several histologic types of malignant periapical lesions that could be mimicking endodontic pathoses. Because these lesions usually do not show clinical or radiologic features of malignant alteration, clinicians should consider these hypotheses in their routine.