3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins’ CNS effects have been reported clinically, few studies to date have compared multiple statins’ neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0–100 μM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration. To achieve this, HAPI microglia were treated with LPS (0.1 μg/mL; 24 h), resulting in increased reactive oxygen species (ROS), nitric oxide, and IL-1β TNF-α and PGE2 release. Conditioned media (“HAPI-CM”) was then transferred to SH-SY5Y neuroblastoma cells, and effects on cellular viability, mitochondrial membrane permeability, apoptosis, autophagy and ROS production assessed. Of the statins investigated, only atorvastatin, pravastatin and rosuvastatin protected SH-SY5Y cells from LPS-induced decreases in cellular viability; this appeared mediated through reduced caspase 3/7 activation and was associated with decreased IL-1β (atorvastatin, pravastatin) and/or TNF-α (atorvastatin, pravastatin, rosuvastatin). Only pravastatin conferred protection at all tested concentrations. ROS production and autophagic vacuole formation was decreased by all statins, suggesting these two mechanisms are unlikely to be sole mediators of neuroprotection seen with selected statins. Ultimately, our model suggests that despite all statins reducing microglial inflammation, subsequent effects on neuronal viability and cell death signalling pathways varies between statins. Our findings highlight the need to consider individual statins as inducing discrete pharmacological effects within the CNS in future in vitro/in vivo studies and in clinical practice.