Background: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by fluctuating activity affecting multiple organ systems. Timely and accurate assessment of disease activity is critical for guiding clinical decisions and implementing treat-to-target strategies. The Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) is a recently developed, continuous, and weighted index for disease activity, though it has not yet been validated in Russian patients. Objective: To validate SLE-DAS in a Russian cohort of patients with SLE. Methods: We prospectively enrolled 200 SLE patients followed for ≥12 months at the V.A. Nasonova Research Institute of Rheumatology. The median age was 35.0 [26.0–43.0] years; 84.5% were female. Median disease duration was 63.0 [22.0–158.0] months. Clinical and laboratory data were analyzed to asses SLE-DAS performance. Internal consistency of SLE-DAS was assessed using Cronbach’s alpha. Convergent validity was evaluated via correlation with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and Physician Global Assessment (PGA). To compare the ability of SLE-DAS and SLEDAI-2K to identify active SLE, we performed a receiver operating characteristic (ROC) analysis with determination of the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Cohen’s kappa. Responsiveness was analyzed using the Wilcoxon test, SRM, and Cohen’s d. Results: At baseline, the median SLEDAI-2K was 8.0, PGA 0.99, and SLE-DAS 8.38. SLE-DAS showed excellent convergent validity (ρ = 0.878 with both SLEDAI-2K and PGA). Internal consistency was moderate for binary components (α = 0.663), while quantitative variables showed low agreement. According to DORIS remission framework, 90.5% of patients had active SLE. ROC analysis showed high diagnostic accuracy: AUC = 0.899 for SLE-DAS and 0.870 for SLEDAI-2K. After reclassifying 23 patients on glucocorticoids >5 mg/day without clinical activity as inactive, SLE-DAS showed superior performance: AUC = 0.973, sensitivity 96.2%, specificity 97.6%, PPV 99.3%, NPV 82.4%, κ = 0.86. Responsiveness at 6 and 12 months was also confirmed (SRM = –0.78 and –0.66, both p < 0.0001). Conclusion: SLE-DAS is a valid, responsive, and accurate tool for assessing SLE activity in Russian patients and may improve clinical monitoring in routine practice.