INTRODUCTION: Health-related quality of life (HRQoL) is crucial in marital well-being, especially in contexts like Iran where traditional values and religious beliefs strongly influence family dynamics. While quality-of-life research is broad, there is a specific gap in understanding how spirituality and gender roles impact HRQoL in Iranian married couples. This study aims to fill the gap by investigating how spirituality and gender moderate the association between family functioning and HRQoL. METHOD: A survey was conducted with 371 married couples in Iran, using a cross-sectional approach. The Family Assessment Device was used to assess family functioning, the World Health Organization quality of life-BREF questionnaire was utilized to measure HRQoL, and spirituality was gauged with the Spiritual Value questionnaire. To reduce the influence of common method bias, the study utilized Harman's single-factor test. The impact of moderators was then examined through the use of partial least squares structural equation modeling. RESULTS: Findings showed no significant common method bias. Factors such as problem-solving, family roles, behavioral control, and general family functioning were found to have a positive influence on HRQoL. In contrast, family communication, affective involvement, and affective responsiveness were not significant predictors of HRQoL. Spirituality moderated the association between HRQoL problem-solving and general family functioning. Gender did not moderate the association between family functioning and HRQoL. DISCUSSION: These findings highlight the significance of family dynamics and spirituality in shaping HRQoL in non-Western settings. They emphasize the importance of conducting more research on the quality of life in married couples in various cultural and societal settings. (PsycInfo Database Record (c) 2025 APA, all rights reserved).