Background Osteoarthritis is one of the most common musculoskeletal problems. Pain is the most common complaint and the most significant cause of decreased health-related quality of life (HRQOL) among osteoarthritic patients. The objectives of this study were to assess the impact of pain on quality of life among patients with osteoarthritis and to assess the association of sociodemographic and clinical factors with HRQOL. Methods Using a cross-sectional study design, we collected data from osteoarthritis patients in orthopedic outpatient clinics from four hospitals in the Palestine-West bank between November 2020 and March 2021. We used the Brief Pain Inventory (BPI) scale to assess pain and the Quality of Life scale five dimensions (EQ-5D) with the visual analog scale of the European Quality of Life (EQ-VAS) to assess HRQOL. Results In our study, 196 patients composed the final sample, with an average of 60.12 ± 13.63 years. The medians for the EQ-5D score and EQ-VAS score were 0.72 (0.508–0.796) and 70 (55–85), respectively. The pain severity score was found to have a significant negative association with both the EQ-5D and EQ-VAS scores with r of − 0.620, p <  0.001, and − 0.554, p <  0.001, respectively. Similar associations were found between pain interference score and both EQ-5D (r = − 0.822, p <  0.001) and EQ-VAS scores (r = − 0.609, p <  0.001). Multiple regression analysis showed that participants with higher educational level (p = 0.028), less diseased joints (p = 0.01), shorter duration of disease (p = 0.04), and lesser pain severity and interference scores (both with p < 0.001) had significantly higher HRQOL scores. Conclusions We found that many variables have a significant negative impact on HRQOL among patients with osteoarthritis. Our finding provides a well-founded database to use by clinicians and healthcare professionals who work with patients with osteoarthritis, as well as educational and academic institutions.