Extensive use of silica nanoparticles (SiNPs) in biomedical and industrial fields has increased the risk of exposure, resulting in concerns about their safety. However, information regarding their neurotoxic effects through different pathways particularly by perturbing the oxidative/nitrosative balance and causing striatum damage is scarce. The objective of this study was to further assess mechanisms involved in SiNPs-induced neurotoxicity in the striatum using a rat model. Results showed a significant increase in lipid peroxide levels (LPO), reactive oxygen species (ROS), nitrite (NO) and protein carbonyl contents in the striatum, whereas there was a significant decrease in antioxidant enzyme activities (SOD, CAT and GPx) and glutathione (GSH) levels in rats following a subacute intraperitoneal injection of SiNPs (at 25 and 100 mg/kg bw/day for 28 days) compared to controls. Furthermore, a decrease in cholinergic (AChE and BChE) and membrane-bound ATPase (Na+ K+ ATPase, Mg2+ ATPase and Ca2+ ATPase) enzyme activities in the striatum was also observed. Immunohistochemical analyses of the striatum revealed a significant increase in protein expression of antioxidant markers, in particular nuclear factor erythroid-2-related factor-2 (Nrf2) and Heme oxygenase-1 (HO-1). Quantitative real-time PCR also showed that SiNPs induced an up-regulation of pro-apoptotic gene expression (Bax, p53, Caspase-9/3) and down-regulation of anti-apoptotic factor Bcl-2 in this brain region, with a concomitant upregulation of the Bax/Bcl-2 ratio. Histopathological analysis confirmed that SiNPs induced extensive neuronal damage and degeneration of surrounding cells in striatum tissue. Our findings suggest that oxidative/nitrosative stress-mediated apoptosis is involved in the striatum neurotoxicity induced by SiNPs by activating Nrf2/HO-1 and apoptotic signaling pathways.