Depression is a common serious mood disorder, which spread all over the world and the leading cause of disability. It is mainly characterized by loss of interest and hope in life. Despite decades of research, the pathophysiology of depression remains incompletely understood. So understanding the pathophysiology of depression is crucial to develop effective treatment strategies, which helps in the improvent of patient's quality of life and prevents the recurrence. In this review, different mechanisms contributing to the onset, progression and persistence of depressive symptoms are explained; such as neurotransmitters imbalances, particularly serotonin, norepinephrine and dopamine as well as neuroinflammation, endocrine disturbances, genetic predisposition, neurostructural changes, Glutamatergic and GABAergic alterations, and finally circadian rhythm disturbances. All these mechanisms were found to involve in the pathophysiology of depression but unfortunately it varies between patients, so further studies are required to know much more about the intricate mechanisms and thus develop novel treatments that can make a breakthrough in the treatment and prevention of depression.