Neuroplasticity is characterized by the brain's ability to change its activity in response to extrinsic and intrinsic factors and is thought to be the mechanism behind all brain functions. Neuroplasticity causes structural and functional changes on a molecular level, specifically the growth of different regions in the brain and changes in synaptic and post-synaptic activities. The four types of neuroplasticity are homologous area adaption, compensatory masquerade, cross-modal reassignment, and map expansion. All of these help the brain work around injuries or new information inputs. In addition to baseline physical functions, neuroplasticity is thought to be the basis of emotional and mental regulations and the impairment of it can cause various mental illnesses. Concurrently, these mental illnesses further the damage of synaptic plasticity in the brain. Major depressive disorder (MDD) is one of the most common mental illnesses. It is affected by and accelerates the impairment of neuroplasticity. It is characterized by a chronically depressed state of mind that can impact the patient's daily life, including work life and interests. This review will focus on highlighting the physiological aspects of the disease and the role of neuroplasticity in the pathogenesis and pathology of the disorder. Moreover, the role of monoamine regulation and ketamine uptake will be discussed in terms of their antidepressant effects on the outcomes of MDD.