Depression is a complex psychiatric disorder with growing evidence linking its pathogenesis to oxidative stress. Oxidative stress is mainly defined by an imbalance between the body’s antioxidant mechanism and production of reactive oxygen species (ROS), which leads to cellular damage and dysfunction. This imbalance affects major critical cellular process in the brain like mitochondrial function, neurotransmitter regulation, and synaptic plasticity which are a vital cellular process for maintaining mental health. Mitochondrial dysfunction because of oxidative stress results in energy deficits in neurons promoting impairing neurogenesis and neurodegeneration which leads to depressive behavior. Moreover, oxidative stress activates proinflammatory signaling pathways which contribute to the neuroinflammatory environment seen in depression. This chapter deals with the molecular mechanisms which disrupt neuronal function and structure via oxidative stress emphasizing its role in neurotransmitter system modulation, including serotonin, dopamine, and glutamate which control mood regulation. This chapter also explores the other potential antioxidants and other therapeutic agents restoring neuronal health by mitigating oxidative stress, highlighting innovative treatment strategies against depression. By countering the mechanistic action against oxidative stress during depression, this chapter aims to provide a clear understanding of its role in the disease process and to identify potential targets for therapeutic intervention.