Estradiol, the primary estrogen hormone in females, plays a crucial role in the regulation of synaptic function and neuroinflammation within the central nervous system. The present study is aimed to investigate the effect of estradiol on mRNA expression of synaptic proteins and neuroinflammatory markers in unilateral and bilateral ovariectomized rat models, a commonly used method to induce estrogen deficiency and study the consequences of hormonal changes. Two months old Wistar albino female rats were divided into five experimental groups, each consisting of 6 animals. Unilateral and bilateral ovariectomized rats were treated with estradiol (10 mg/Kg/b.wt) subcutaneously for 30 days. A significant decrease was observed in the mRNA levels of Synuclein, SNAP25, PSD-95, Neuroligin, and MMP-9 along with a significant increase in the expression levels of IL-6 both in unilateral and bilateral ovariectomized rat models, indicating potential disruptions in synaptic function and neuronal plasticity. Furthermore, the bilateral ovariectomy group exhibited a more pronounced decrease when compared to the unilateral ovariectomy group. Moreover, when comparing the expression levels of these genes between the unilateral and bilateral ovariectomy groups after estradiol treatment, we observed a significant increase in Synuclein, SNAP25, PSD-95, Neuroligin, MMP-9 expression along with a significant decrease in the mRNA levels of IL-6 in the unilateral ovariectomy group compared to the bilateral ovariectomy group. The findings suggest that estradiol plays a crucial role in regulating synaptic function, neuroprotection, inflammation, and cognitive processes. Understanding the molecular mechanisms underlying estradiol's effects on gene expression in these genes may contribute to the development of therapeutic interventions for conditions associated with estrogen deficiency.