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This essay investigates the role of cortisol as a central regulator of neuronal plasticity, considering physiological, molecular, and hormonal aspects. Neuronal plasticity is a continuous and dynamic process, essential for the adaptation of the nervous system throughout life. We explore how cortisol, acting as a transcription factor, modulates the expression of key genes that directly affect neuronal metabolic pathways, including ATP production in mitochondria, energy homeostasis, and the activity of neurotransmitters such as glutamate and GABA. We highlight specific genes modulated by the cortisol-GR complex and how this regulation impacts processes such as mitochondrial biogenesis, protection against oxidative stress, and the maintenance of synaptic plasticity. This study proposes an integrated view of how gene regulation and cortisol action are key to synaptic remodeling, excitatory-inhibitory balance, and stress adaptation, providing a solid foundation for understanding brain resilience and plasticity under adverse conditions.