Background: Disrupted iron homeostasis is increasingly perceived as a key driver of major depressive disorder pathogenesis; hence, targeting ferroptotic cascades may reveal novel therapeutic targets. This study evaluated the neuroprotective potential of the oral iron chelator deferasirox (DEF) against chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive deficits in Wistar rats. Methods: We specifically explored whether DEF could provide neuroprotection by targeting ferroptotic and oxidative stress pathways. Male Wistar rats were exposed to a 6-week CUMS protocol and treated with DEF (10, 20, or 40 mg/kg). Results: CUMS-exposed rats exhibited significant anhedonia, behavioral despair, and impaired spatial and recognition memory. Further analyses revealed a reduction in colonic and choroid plexus occludin, reflecting compromised structural integrity of both the intestinal and blood-CSF barriers, accompanied by enhanced hippocampal iron accumulation with increased Acyl-CoA synthetase long-chain family member 4 (ACSL4), Acyl-CoA synthetase family member 2 (ACSF2), and citrate synthase expression, alongside exaggerated oxidative stress and deficient neuroprotective mediators, specifically BDNF and synaptophysin, and increased neurofibrillary tangle (NFT) deposition, collectively exacerbating neurodegenerative pathology. DEF treatment ameliorated most of these effects, significantly reducing iron deposition, attenuating ferroptosis-related signaling, reducing oxidative stress, diminishing the ongoing neurodegeneration, and replenishing the depleted pool of BDNF and synaptophysin, which was accompanied by a reduction in depressive-like symptoms and improved cognitive functions. Conclusions: These findings support a link between ferroptosis-related signaling and depression-like phenotypes, reinforcing the concept of a metal-driven component in depression pathophysiology and offering a mechanistic rationale for further exploring targeting ferroptotic pathways and central iron regulation as potential targeted strategies in depression management.