Schizophrenia is a mental disorder in which perception and thought are severely impaired.It affects approximately 20 million people worldwide, with high suicidal rates and a high annual incidence of 1.5 per 1000 people. There are many hypotheses that define the pathogenesis of Schizophrenia (SCZ) among which excessive activation of dopamine (D2) receptors via the mesolimbic pathway, while low levels of dopamine in the nigrostriatal pathway are widely accepted. The hypothesis discusses the role of dopamine in causing alteration in the calcium homeostasis. Dopamine, N-methyl-D-aspartate (NMDA) receptor dysregulation and calcium homeostasis has been extensively studied to understand the mechanisms of neurodegeneration observed in Schizophrenia. Involvement of dopamine and NMDAR with the calcium and calcium ion channels on plasma membrane, endoplasmic reticulum, and mitochondria of the neuronal cells to form the vicious circle of calcium load. The disruption in the calcium homeostasis accompanies changes as observed in the whole brain pathology of SCZ. This includes synaptic dysfunction, impaired cognition, mitochondrial dysfunction, oxidative stress, inflammation, and cell apoptosis. This presents an immense need for the variety of potential therapeutic targets that could prevent or slow the progression of Schizophrenia. This review deals with the comprehensive source of information about mechanisms through which dopamine and NMDAR interacts with various calcium ion channels and the beneficial effect of calcium ion channel modulator in Schizophrenia.