Background <p>Hydroxychloroquine is increasingly being used to treat primary glomerular diseases. It has shown promising results in terms of reducing proteinuria and stabilizing kidney function. This systematic review aimed to assess the effects of HCQ on proteinuria and the estimated glomerular filtration rate (eGFR) in primary glomerular diseases and evaluate its safety profile.</p> Methods <p>A literature search was conducted using PubMed, ScienceDirect, Springer, and Google Scholar for articles published between 2014 and 2024. Articles incorporating hydroxychloroquine for the treatment of primary glomerular diseases were considered. These studies evaluated the effect of HCQ on 24-hour proteinuria and eGFR. Pooled mean differences (MDs) and heterogeneity metrics (Tau², I², and Q-test) were analysed. The safety data from all included studies were reviewed.</p> Results <p>HCQ administration significantly reduced proteinuria (MD = -0.69, 95% CI= -0.79 to -0.59), with pronounced effects for longer treatment durations (MD = -0.74, 95% CI= -0.81 to -0.67), and in patients with membranous nephropathy (MD = -3.00, 95% CI= -4.46 to -1.53). Conversely, no significant improvement in eGFR was observed after HCQ treatment (MD = -1.03, 95% CI= -2.73 to − 0.67). A beneficial effect was noticed in patients with IgA nephropathy (MD = -2.65, 95% CI= -5.16 to -0.14). Moderate to substantial heterogeneity (I² = 69–95%) was observed for proteinuria outcomes, but no heterogeneity was found for eGFR outcomes (I² = 0%). 69 adverse events were reported, of which gastrointestinal and mucocutaneous effects were the most common.</p> Conclusion <p>HCQ therapy for primary glomerular diseases showed a trend toward reducing proteinuria without significant effects on eGFR, with a better safety profile.</p> Trial registration <p>This systematic review was registered in PROSPERO with ID CRD42024597762.</p>