Adolescent depression is increasingly prevalent, and the ongoing neurodevelopmental remodeling of the adolescent brain confers heightened vulnerability to stress. Accumulating evidence indicates that stress acts as a primary upstream driver that converges on synaptic dysfunction through tightly interconnected metabolic, inflammatory, and redox pathways. Across prenatal, early-life, and adolescent stress models, stress exposure disrupts synaptic maturation and emotional regulation, with maternal stress and intergenerational effects further amplifying risk during adolescence. At the mechanistic level, stress-induced mitochondrial dysfunction and impaired energy metabolism initiate oxidative imbalance, leading to excessive reactive oxygen species accumulation and weakened antioxidant capacity. These metabolic disturbances synergize with neuroimmune activation—characterized by microglial reactivity, inflammasome signaling, and pro-inflammatory cytokine release—to destabilize synaptic structure and plasticity. Concurrently, dysregulated iron homeostasis exacerbates oxidative damage and ferroptosis-related processes, reinforcing a self-propagating pathological loop that converges on impaired synaptic plasticity, including deficits in long-term potentiation/long-term depression, dendritic spine maintenance, and neurogenesis. Together, these findings support a unified stress–metabolism–inflammation–iron–synapse cascade underlying adolescent depression. Future studies should focus on resolving causal relationships, delineating developmental stage–dependent amplification effects, and integrating multi-omics with clinical evidence to inform early, mechanism-guided interventions and prevention strategies.