Abstract Background We aimed to investigate the determinants of Health-related quality of life (HRQOL) in Iranian patients with celiac disease (CD) using the structural equation modeling (SEM). Methods In the present cross-sectional study, a total of 170 adult patients with CD were recruited. The information regarding adherence to diet, symptom severity, and HRQOL were collected using the celiac disease adherence test (CDAT), gastrointestinal symptom rating scale (GSRS), and SF-36 questionnaire respectively. Association between various studied variables and HRQOL was assessed using SEM. The standardized regression weights were used to assess total, direct and indirect effects. The model fit indices were used to assess the “goodness of fit” between the hypothesized models. Results The mean age of participants was 37.57 ± 9.59 years. The results of SEM indicated that the overall fit of our model was acceptable. Adherence to the diet, GSRS score, occupation, and education level was significantly related to PCS of SF-36; and adherence to the diet, GSRS score, and education level were significantly correlated with MCS of SF-36. The analysis of indirect associations indicated that only adherence to diet indirectly via GSRS score was significantly associated with PCS and MCS of SF-36. Conclusion In adult patients with celiac disease, HRQOL was associated with age, education, adherence to GFD, and GSRS score. Additionally, occupation and disease duration were associated with HRQOL only in women and men respectively.