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Previous studies have observed a correlation between plasma gelatinase-associated lipocalin (NGAL) levels and cognitive function in drug-naïve patients with schizophrenia (DNS), but the mechanism is unclear. Basic research suggests that the neuroprotective effect of NGAL may be related to the regulation of growth factors. So, we hypothesized that growth factors such as brain-derived neurotrophic factor (BDNF) mediated the effect between NGAL and cognitive function in DNS. This study recruited 137 DNS patients and divided the patients into severe cognitive impairment group (SCI-DNS, n = 58) and non-SCI group (non-SCI-DNS, n = 79) according to the MATRICS Consensus Cognitive Battery (MCCB), with SCI defined as MCCB composite T-score < 25. Sociodemographic characteristics, cognitive function, psychotic symptoms and peripheral blood samples were collected from all participants. Plasma levels of NGAL, BDNF, epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay (ELISA). (1) SCI was observed in 42.3% of DNS. (2) Plasma levels of NGAL, BDNF, and EGF were significantly lower in the SCI-DNS group compared with the non-SCI-DNS group. (3) Plasma NGAL exhibited significant positive correlations with all three growth factors (BDNF, EGF, VEGF). (4) Plasma NGAL, BDNF, and EGF levels were positively associated with cognitive function. (5) Plasma BDNF demonstrated a significant mediating effect in the relationship between plasma NGAL and cognitive function. In patients with DNS, those with SCI exhibited lower plasma levels of NGAL, BDNF and EGF. Notably, a significant BDNF-mediated pathway was identified in the association between NGAL and cognitive function.