Designer drugs are synthetically formulated to mimic the psychostimulatory effects of an original controlled/illegal drug of abuse. Designer drugs have similar chemical structure or functional analog as compared to existing controlled psychostimulatory drugs. There is a substantial rise in the production and use of designer drugs globally. Piperazine designer drugs were synthesized as an alternative to MDMA and have shown to induce numerous toxic effects leading to huge health, safety, law enforcement & monetary problems, and lethality. Currently, there are very few studies on the dopaminergic neurotoxicity of 1-(3-trifluoromethylphenyl) piperazine (3-TFMPP) and its derivatives (structural congeners). N27 rat dopaminergic neurons are valid cells to investigate the neurotoxic effects and establish the neurotoxic mechanisms of various substances. In the current study, we studied the time and dose-dependent neurotoxicity mechanisms of dopaminergic neurotoxicity of 3-TFMPP (parent compound) and its derivatives (2-TFMPP, 4-TFMPP). TFMPP derivatives-induced significant neurotoxicity (induced dopaminergic neuronal death. TFMPP derivatives-induced oxidative stress, mitochondrial dysfunction, apoptosis and decreased tyrosine hydroxylase expression. If the use of designer drugs are not strictly regulated and restricted around the world, this can lead to numerous central and peripheral disorders leading to a liability to the current and future society.