Background and Objectives: Phenylketonuria (PKU) is an inherited metabolic disease that requires lifelong treatment and management. PKU disease affects the quality of life of patients and their caregivers and also challenges the adaptation and psychological well-being of parents. Therefore, the current review study was conducted with the aim of identifying the factors related to the psychological well-being of these parents. Materials and Methods: This study is a systematic review. Searching for related articles was done in the period from 2001 to 2022 in foreign electronic databases such as Scopus, Science Direct, PubMed, Google Scholar, and SID and Magiran internal databases using the Persian keywords “phenylketonuria, parents, psychological well-being, and Quality of life”, and their English equivalents. The search criteria included studies with more than one sample, studies that used the official measure of psychological functioning related to the well-being of these parents, and full articles published in Persian and English. Results: In the initial search, 334 articles were found, after removing duplicates and including inclusion criteria, finally 24 articles were examined in line with the objectives of the present study. The findings showed that the demographic variables such as parent's gender and education level, child's age, and family income were the most extensive factors related to the well-being of these parents. Social support and variables of quality of life, stress, and psychological distress were the next repeatable factors related to parents’ well-being. Conclusion: These results show the importance of social networks in supporting families, especially mothers with PKU children. Future research should focus on using more diverse study designs and larger samples. Interventional studies may help improve parental well-being.