Depression is a mental disorder of global concern, with chronic psychological stress being one of the underlying predisposing factors. This study evaluated the role of the antioxidant, N-acetylcysteine (NAC), as an antidepressant using the forced swim test (FST) animal model. Thirty adult male Wistar rats (250 g average weight) were randomly grouped into six (n=5): Control (1 ml/day of normal saline); FST model; NAC (200 mg/kg/day); Fluoxetine (20 mg/kg/day); FST model treated with NAC (200 mg/kg/day), and FST model treated with Fluoxetine (20 mg/kg/day). All the treatments were orally. The FST, sucrose-preference test (SPT), and brain weights were assessed, and data analysed. The histo-architecture of the prefrontal cortex (PFC), as well as the immunohistochemistry of astrocytes and synaptophysin were also assessed. Findings showed that NAC prevented FST-induced depressive behaviour demonstrated by increased SPT and mobility time. NAC also prevented the FST-induced decreased brain weights and neuronal loss, reduced proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that of fluoxetine, a standard antidepressant drug. NAC exhibited its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, and protecting neurons and synapses from oxidative tissue damage induced by FST, hence, an increase in synaptophysin activity that culminated in increased neural activity, increased SPT, and reduced immobility time.