Objective <p>This study aimed to assess determinants of health-related quality of life among patients with rheumatoid arthritis in northwest Ethiopia in 2025.</p> Method <p>A multi-center cross-sectional design was employed. A systematic random sampling technique was utilized to collect data. Face-to-face interviews with respondents from selected hospitals were conducted to gather data. The analysis was performed on a sample of 422 rheumatoid arthritis patients randomly selected from a total of 5280 across six comprehensive specialized hospitals in northwestern Ethiopia. Multiple linear regression was used to identify associated factors. Statistical significance was set at <i>P</i>-value &lt; 0.05.</p> Result <p>The summaries of the physical and mental components had mean scores of 30.7 (SD, 11.35) and 43.5 (SD, 12.01), respectively. The physical component summary was negatively associated with being uneducated (<i>β</i> = − 0.14, 95% CI (−4.03,−0.04)), high disease activity (<i>β</i> =−0.63, 95% CI (−20.70,−11.95)), and unavailability of medication (<i>β</i> = − 0.24, 95% CI (−5.23,−1.45)). Being employed was positively associated (<i>β </i>= 0.12, 95% CI (0.08, 4.81)). The mental component summary was negatively associated with obesity (<i>β </i>= −0.18, 95% CI (−9.62,−0.45)), high disease activity (<i>β </i>= −0.55, 95% CI (−20.45,−9.95)), marital status (<i>β</i> =−0.21, 95% CI (−5.79, −1.12)), and unavailability of medication (<i>β</i> = −0.12, 95% CI (−6.31,−1.54)).</p> Conclusion <p>Overall, the study revealed that health-related quality of life was poor. Rheumatoid arthritis patients' physical health-related quality of life was more affected than their mental quality of life. Factors such as being single, disease activity, medication availability, and disease duration influence health-related quality of life. Prioritizing therapeutic education and medication availability for patients with long-standing disease and high disease activity is crucial to improving health-related quality of life.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>Poor health-related quality of life: Patients with rheumatoid arthritis (RA) in North West Ethiopia experience significantly low health-related quality of life, particularly in physical health</i>.</p> <p>• <i>Determinants identified: Key factors affecting quality of life include marital status, disease activity, obesity, medication availability, and duration of illness, with single and obese patients particularly affected</i>.</p> <p>• <i>Need for education and access: Emphasizing therapeutic education and ensuring medication availability for patients with prolonged disease duration and high disease activity is vital for improving health outcomes</i>.</p> <p>• <i>Healthcare recommendations: Targeted public health interventions should address socio-demographic influences and enhance health literacy among RA patients to improve their quality of life</i>.</p> </entry> </row> </tbody> </tgroup> </Table></p>