•There is a correlation between environmental particulate matter and health effects.•We studied in vitro simvastatin’s potential protective effect on ROFA cytotoxicity.•ROFA decreased cell viability, increased ROS generation, apoptosis and senescence.•Pretreatment with simvastatin attenuated the adverse effects observed.•Simvastatin may provide protection against particulate matter-induced neurotoxicity. Epidemiological studies have shown a positive correlation between environmental particulate matter and adverse health effects. In particular, residual oil fly ash (ROFA) induces inflammation and reactive oxygen species (ROS), exerting not only local, but also systemic adverse effects. Previously, in an experimental animal model, we found that simvastatin (Sv) pretreatment was effective in preventing ROFA induced lung inflammation. Herein, using the human neuroblastoma SH-SY5Y cell line as a neurotoxicity in vitro model, we studied the potential Sv protective effect on ROFA cytotoxicity. We evaluated cell viability by the MTT assay, superoxide anion generation by NBT test, Nrf2 activation by immunofluorescence, apoptosis by cleaved-PARP and active-caspase 3 expressions, and senescence by β-galactosidase activity. SH-SY5Y cells exposed to ROFA (10 and 50μg/ml) for 24h showed decreased cell viability, increased superoxide anion generation, apoptosis and senescence. Pretreatment with Sv (1μM) for 6 days, restored cell viability to basal levels, reduced ROFA-induced O2− generation as well as the number of apoptotic and senescent cells. Sv pretreatment stimulated the basal and ROFA-induced levels of Nrf2 nuclear translocation suggesting that activation of the cellular antioxidant defense system prevented particle-induced oxidative stress. In parallel, rescue experiments with mevalonate did not modify the effects of SV pretreatment in any of the parameters evaluated in this study. We conclude that simvastatin may provide neuroprotection against air particulate matter-induced neurotoxicity independently of its ability to inhibit cholesterol synthesis.