Piperazine is a six-membered heterocyclic ring with two nitrogen atoms at positions one and four. This piperazine moiety can be present in a slew of well-known medicines that have pharmacophoric effects on a variety of receptors. Various piperazine analogs have core biological activities involving the activation of monoamine pathways, primarily on neurotransmitter receptors. As a result, piperazine analogs have a wide range of central clinical uses, including anxiolytic, antipsychotic, and antidepressant. Due to its stimulant and euphoric effects, benzyl-piperazine is the prototype of piperazine analogs, and this molecule is the main substance of recreational drugs. This review focuses on the activity of piperazine pharmacophore on diverse neurotransmitter receptors used therapeutically as anxiolytics (buspirone), antidepressants (vortioxetine), antipsychotics (clozapine), and other drugs.