The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug. Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC). Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug. NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.