Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role as a transcription factor at the heart of cellular defense mechanisms against oxidative stress, orchestrating a suite of cytoprotective genes. This review places particular emphasis on the interplay between Nrf2 and Sirtuins-NAD-dependent deacetylases integral to redox regulation, metabolic control, and neuroprotection. We highlight how these proteins cooperate to regulate oxidative defense and cellular metabolism, with a particular focus on brain physiology and resilience. We briefly touch on the regulatory influence of specific microRNAs (e.g., miR-126, miR-34a) as emerging modulators of this pathway. Through this review, we aim to consolidate insights into Nrf2-Sirtuin crosstalk, particularly in the context of brain health, and highlight potential therapeutic strategies including pharmacological agents, miRNA modulators, and ischemic preconditioning mimetics. This work aims to inspire further investigation and translational advances in the treatment of oxidative stress-related neurological disorders.