Introduction: The burden associated with rheumatoid arthritis (RA) is substantial, leading to pain, suffering, impaired physical function, disability and deterioration in quality of life of the patients. Very few studies evaluating health-related quality of life (HRQOL) and its determinants have been published among RA patients in Southern India. The aim of the present study is to investigate the various dimensions of HRQOL and its relationship with various sociodemographic characteristics, functional status and disease activity using a structural equation modeling (SEM) approach in patients with RA. Materials and Methods: A cross-sectional study was conducted among 110 patients attending tertiary care teaching hospital. SF 36 was used to assess the HRQOL. Disease activity score-28 (DAS28) was used to measure the disease activity and Health Assessment Questionnaire Disability Index (HAQ-DI) was used for measurement of functional disability. SEM analysis was performed to test and evaluate the structural relationships of the model using R Programming. Results: The mean age of patients was 44.85 ± 11.25 years and 92 (83.6%) were female. Lower HRQOL scores were obtained in the domain of role functioning/physical 48.86 (±40.55), general health 48.27 (±14.92) and physical functioning 40.45 (±23.76). SEM results showed that HAQ–DI and DAS28 were covariance with each other (r = 0.54, P = 0.039), HAQ-DI was a significant predictor of GenPHYS (P = 0.001) and DAS28 was a significant predictor of GenPHYS (P = 0.001) and GenMENT (0.025). Conclusions: Impact of RA was substantial in both physical and mental domains of HRQOL. The functional disability was having an impact on physical health, whereas disease activity was associated with physical and mental health domains of HRQOL.