Objective: Spinal cord injury (SCI) often results in irreversible neurological deficits and poses a critical public health issue. The molecular mechanisms governing cellular responses postinjury remain incompletely understood. Wnt signaling is known to influence neurogenesis and axonal regeneration. In particular, Wnt ligands and their antagonists, such as secreted frizzled-related protein 4 (SFRP4), are differentially expressed following SCI. This study investigated the role of the Wnt3a/SFRP4 signaling axis in regulating neuronal cell fate. Methods: Human neuroblastoma SH-SY5Y and rat pheochromocytoma PC12 cell lines were obtained from the American Type Culture Collection. The metabolic activity of cells—used as a surrogate marker for proliferation—was assessed using the Alamar Blue assay. To mimic neurodegeneration associated with SCI, cells were treated with lipopolysaccharide (LPS). The effects of Wnt3a and SFRP4 were analyzed both individually and in combination under normal conditions and LPS-induced stress. Results: Wnt3a treatment alone significantly increased metabolic activity in untreated and LPS-treated cells, indicating a proliferative effect. However, cotreatment with Wnt3a and SFRP4 reduced proliferation, particularly in the presence of LPS. SFRP4 alone demonstrated variable effects depending on cellular conditions, with some enhancement of metabolic activity in the LPS model but reduced activity when combined with Wnt3a. Conclusion These findings suggest that the effect of SFRP4 on Wnt3a-mediated signaling is context-dependent, potentially promoting proliferation in normal conditions but antagonizing Wnt3a activity under stress. A deeper understanding of the Wnt signalosome and SFRP family interactions could shed light on novel therapeutic strategies for modulating neuroinflammation and promoting repair after SCI.