Extramarital relations are among the main problems in the relationships of married couples that can result in psychological disorders, tensions between couples, and even physical problems in the people involved. The risk of contracting sexually transmitted diseases, including HIV/AIDS, is high among the people who have extramarital relations. A large number of studies have addressed this issue, but there is no consistency in the results, and no research has reviewed them systematically. This study aims to depict a comprehensive image of the relationship between extramarital relationships and contracting HIV/AIDS. This systematic review will be conducted using Pubmed, PsycINFO, MEDLINE, EMBASE, Scopus, ProQuest, Web of Science, and Google Scholar, as well as the grey literature with no restriction regarding the language. All types of studies investigated the relationship between extramarital relations and HIV/AIDS will be included. The population of the study will be considered the people more than 18 years old with extramarital relationships in their lives at the time of research or before. Two independent reviewers will perform the study selection and data extraction. The assessment of the risk of bias will be implemented using the JBI Critical Appraisal Checklist. Publication bias will be assessed by funnel plots, Begg’s, and Egger’s tests. Heterogeneity will be evaluated using the I2 statistic and the χ2 test. Also, we will conduct subgroup analyses for the population and all Meta-analyses will be performed using Stata V.13 software. The findings will reveal a comprehensive picture of the relation between extramarital relationships and HIV/AIDS that can improve policy decisions, leading to a reduction and providing improved special services for individuals, couples, and families, and society who faced this problem.