As a stressor, social isolation in adolescence can lead to changes in social behavior and neuroendocrine system network function of animals and humans. A large number of studies have found that exposure to social isolation stress can induce specific changes in the function of different areas of the brain, active the hypothalamic-pituitary-adrenal axis, synthesize and release neurotransmitters such as dopamine, serotonin, γ-aminobutyric acid, and glutamate, and change the sensitivity of their receptors. These changes can induce different degrees of depressive-like behavior in animals and humans, which is closely related to the occurrence of depression. Adolescence is a critical period for neural networks, function and chemical reorganization of the brain, and compared with social isolation in adulthood, adolescent social isolation has a sustained and irreversible negative impact, greatly increasing the risk of mental illness in individuals. This article reviews the brain mechanisms associated with depression caused by social isolation in adolescence, discusses the specific effects of adolescent social isolation on brain development, endocrine, neurotransmitters, and glial cells, and discusses its association with depression.