Parents of children with congenital heart disease (CHD) experience higher rates of stress compared with the general population, which adversely affects their health-related quality of life (HRQoL). The purpose of this cross-sectional study was to examine coping strategies as mediators and moderators between perceived stress and HRQoL in parents of children with CHD. The effects of sociodemographic factors on perceived stress and HRQoL were also explored. Parents of children with CHD were recruited to participate from October 2023 to July 2024. Participants completed a self-report, online questionnaire containing the Perceived Stress Scale (PSS), Brief COPE, PedsQL Family Impact module, and the Protocol for Responding to and Assessing Patients Assets, Risks, and Experiences (PRAPARE). SPSS v27.2 and the PROCESS macro extension were used for analysis of mediator and moderator effects of coping strategies. Participants included 53 parents who met criteria and agreed to participate in the study. Parents with Medicaid and other non-private insurance types had higher PSS scores than parents with private insurance. Avoidant coping, self-blame, and behavioral disengagement were positively correlated with PSS and negatively correlated with HRQoL. Regression analysis indicated that coping strategies did not directly mediate the relationship between PSS and HRQoL. Problem-focused coping, active coping, emotional support, acceptance, and self-distraction moderated the effects of PSS on HRQoL. More research is needed to develop and test evidence-based coping interventions that reduce stress and improve HRQoL in parents of children with CHD.