<p>Fibrinogen-like protein 2 (FGL2) has been reported to modulate the tumor microenvironment and play critical roles in the initiation and progression of various tumors. However, its role and underlying mechanisms in neuroblastoma remain unclear. This study aimed to investigate the function of FGL2 in regulating the proliferation, migration, and invasion of neuroblastoma cells. FGL2 expression in neuroblastoma specimens was assessed using immunohistochemistry, polymerase chain reaction, and western blotting. The prognostic value of FGL2 in patients with neuroblastoma was evaluated using Kaplan–Meier survival analysis. Cell Counting Kit-8, colony formation, wound healing, and Transwell invasion assays were performed to assess cell proliferation, migration, and invasion following FGL2 knockdown. The potential molecular mechanisms were explored by western blotting to examine changes in signaling molecules after FGL2 silencing. The results showed that both protein and messenger RNA levels of FGL2 were significantly lower in high-risk neuroblastoma samples compared with non-high-risk samples. Low FGL2 expression was significantly associated with advanced International Neuroblastoma Staging System stage, high-risk classification, and poor survival status. Kaplan–Meier analysis further revealed that patients with low FGL2 expression had significantly worse survival outcomes. Functionally, Cell Counting Kit-8 and colony formation assays demonstrated that FGL2 knockdown increased the viability of neuroblastoma cells, whereas wound healing and Transwell assays confirmed that silencing FGL2 significantly enhanced migratory and invasive capacities compared with control cells. Mechanistically, FGL2 suppressed cell proliferation, migration, and invasion by regulating the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway. These findings suggest that FGL2 may serve as both a prognostic biomarker and a potential therapeutic target in neuroblastoma.</p>