|Designer drugs are synthetic structural analogues/congeners of controlled substances with slightly modified chemical structures intended to mimic the pharmacological effects of known drugs of abuse so as to evade drug classification. Benzylpiperazine (BZP), a piperazine derivative, elevates both dopamine and serotonin extracellular levels producing stimulatory and hallucinogenic effects, respectively, similar to methylenedioxymethamphetamine (MDMA). Here, piperazine derivatives were synthesized in our lab (BZP and BZOP) and the mechanisms of cellular-based neurotoxicity were elucidated in a human neuroblastoma cell line (SH-SY5Y). The principle pathways leading to cellular toxicity include oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, excitotoxicity and necrosis. We evaluated the in vitro effect of benzylpiperazine and benzoylpiperzine on the generation of reactive oxygen species, lipid peroxidation, mitochondrial complex-I activity, catalase activity, superoxide dismutase activity, glutathione content, Bax, caspase-3, Bcl-2 and Tyrosine Hydroxylase expression. BZP and BZOP induced oxidative stress, inhibited complex-I activity and stimulated apoptosis. Prior studies utilizing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), methylenedioxymethamphetamine (MDMA), methamphetamine, paraquat and corexit have established a link between oxidative stress, mitochondrial dysfunction and apoptosis with neurotoxicity. Parkinson’s disease and Alzheimer’s disease are associated with dopaminergic (substantia nigra) and cholinergic (basal forebrain) neuronal cell death, respectively. We postulate that exposure to BZP or BZOP will induce destruction of these pathways resulting in movement disorders and cognitive impairment. This study provides a germinal assessment of the neurotoxic mechanisms induced by piperazine derivatives that lead to cell death.