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Objectives To evaluate longitudinal changes in health-related quality of life (HRQoL) over two years in patients with systemic lupus erythematosus (SLE) and identify determinants of HRQoL trajectories.Methods This prospective cohort enrolled 1,005 SLE patients fulfilling the ACR criteria. HRQoL was assessed using the Short Form-36 (SF-36) questionnaire at baseline, 12, and 24 months. Disease activity and organ damage were measured by the SLE Disease Activity Index-2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index, respectively. Temporal changes in Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were analyzed using generalized estimating equations adjusted for demographic and clinical factors.Results Among 915 women (91.0%), the median age was 35.2 years (IQR 28.1–45.3). Both PCS and MCS scores improved significantly over 24 months (beta = 0.73, 95% CI 0.48–0.98; p < 0.001 for PCS; beta = 0.85, 95% CI 0.57–1.13; p < 0.001 for MCS). Age >= 50 years correlated with lower PCS (beta = –4.2, p < 0.001) but higher MCS scores (beta = 2.1, p = 0.032). Male sex predicted greater MCS improvement (beta = 2.3, p = 0.003) without significant PCS effect. Higher SLEDAI-2K scores were associated with reduced PCS (beta = –0.94, p < 0.001) and MCS (beta = –0.52, p < 0.001) scores. Increasing SLICC damage index independently predicted lower PCS (beta = –1.2, p < 0.001) and MCS (beta = –0.8, p = 0.009) scores.Different organ damage domains exerted distinct effects on HRQoL: musculoskeletal damage had the greatest negative impact on PCS (beta = –3.8, p < 0.001), followed by cardiovascular damage (beta = –2.9, p = 0.001), whereas neuropsychiatric damage had minimal influence (beta = –0.6, p = 0.43). In contrast, organ-specific damage domains did not differentially affect MCS trajectories after accounting for total damage burden.Conclusions HRQoL in SLE patients tends to improve over time, but disease activity, cumulative organ damage, age, and sex significantly shape its trajectory. The novel observation that physical—but not mental—health is differentially affected by specific organ damage domains highlights the importance of domain-based assessment and targeted rehabilitation strategies to optimize long-term outcomes in SLE.