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Objectives Lupus nephritis (LN) is a major determinant of morbidity and mortality in systemic lupus erythematosus (SLE). Although renal biopsy remains the diagnostic gold standard, in areas of limited resources its invasiveness limits its utility for follow-up. This study aimed to identify reliable, non-invasive laboratory predictors of disease activity across different histological classes of LN.Methods A retrospective study included 61 patients (83.6% female; mean age 35.6 ± 10.9 years) with biopsy-confirmed LN hospitalized at the Clinic for Nephrology and Clinical Immunology, University Clinical Center of Vojvodina (2017–2024). Patients were classified according to ISN/RPS criteria (classes II–V). Clinical and laboratory parameters were analyzed in relation to disease activity markers (anti-dsDNA, C3, C4, ESR, CRP, and 24h proteinuria). Three parameter sets were evaluated as potential predictor models: Model 1 – hemoglobin, total proteins, albumin; Model 2 – hemoglobin, total proteins, albumin, fibrinogen; Model 3 – total proteins, albumin, cholesterol, transaminases. Multivariate hierarchical linear regression identified significant predictors for disease activity indices.Results Lower hemoglobin, total protein, and albumin levels, and higher fibrinogen and triglycerides, correlated with greater disease activity. Model 1 showed that total proteins significantly predicted 24h proteinuria (R 2 = 0.331, p < 0.001). In Model 2, total proteins and fibrinogen predicted complement C3 (R2 = 0.174, p = 0.028), while hemoglobin predicted C4 (R2 = 0.089, p = 0.038). Hemoglobin and total proteins were significant predictors of anti-dsDNA titers (R2 = 0.312, p = 0.047). Albumin and fibrinogen together predicted ESR (R2 = 0.292, p = 0.001). Model 3 confirmed triglycerides as an independent predictor of lower C3 and higher anti-dsDNA and ESR levels. Patients with class IV LN exhibited the highest activity, with pronounced anemia, hypoproteinemia, and proteinuria.Conclusions Simple laboratory parameters such as hemoglobin, albumin, total proteins, fibrinogen, and triglycerides reliably reflect LN activity and may complement standard immunological markers. Their integration into predictive models offers a practical, non-invasive approach for assessing and monitoring disease activity in patients with lupus nephritis.