Background: Phenylketonuria is a genetic disorder resulting from lack or inadequacy of phenylalanine hydroxylase enzyme activity. Caring for and making nutritional decisions for a child with phenylketonuria puts a great deal of stress on the parents. Moreover, the financial and psychological burden of the disease as well as its chronic nature could affect the psychological well-being of both parents and their children with phenylketonuria. Aim: to assess the struggles and psychological well-being of parents and their children with phenylketonuria. Subjects & Method: a correlational descriptive study design was conducted on of 145 parents and their children with phenylketonuria. Tools: three tools were used to collect the necessary data for the current study, tool (I): Self-administered questionnaire to collect bio-socio- demographic data, tool (II): Depression, Anxiety, and Stress Scale, tool (III) The Strengths and Difficulties Questionnaire. Results: it was found that 17.9%, 29%, and 15.9% of the participant parents have extremely severe levels of depression, anxiety, and stress respectively. The results also reveal that 64.8%, 59.3%, 53.1%, and 58.6% of the studied children have emotional, conduct, hyperactivity, and peer problems respectively. Moreover, 62.8% of the studied children have a negative impact on different areas of their everyday life related to the difficulties they have. Conclusion: the studied parents struggle to provide care and special foods for their children with phenylketonuria. Behavioral and psychological difficulties facing children with phenylketonuria affect the psychological well-being of their parents. Recommendations: further qualitative studies are needed to provide deep insights into challenges perceived by parents of Phenylketonuria children. Designing and implementing training programs for parents to improve their coping strategies and psychological well-being is mandatory