Geriatric depression is often accompanied by cognitive decline, complicating its diagnosis and treatment. In elderly patients, distinguishing between primary neurodegenerative disorders and depressive pseudodementia remains a major clinical challenge. Esketamine, a rapid-acting N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising treatment for treatment-resistant depression (TRD), with the potential to improve cognitive function. We describe the case of a 79-year-old female patient with a long-standing history of major depressive disorder (MDD) who presented with a moderate-to-severe depressive episode unresponsive to multiple antidepressant treatments. The patient exhibited significant cognitive impairment, raising concerns about underlying neurodegenerative pathology. A comprehensive clinical and neurocognitive evaluation suggested depressive pseudodementia rather than primary dementia. Given her treatment resistance, intranasal esketamine was administered as an adjunctive therapy. Over six months, the esketamine treatment significantly decreased depressive symptoms, as indicated by MADRS, HAMD-21, and HAM-A scores. Cognitive assessments (MMSE and MoCA) showed notable improvements, supporting the hypothesis that effective depression treatment can reverse cognitive deficits associated with pseudodementia. Esketamine was well-tolerated, with minimal side effects, including a transient hypertensive episode that was managed conservatively. This case highlights esketamine’s potential to treat severe depression and the associated pseudodementia in elderly patients. Its rapid onset of action, favorable safety profile, and ability to improve cognitive performance suggest it may be a viable alternative to electroconvulsive therapy (ECT) for geriatric TRD. Further research is needed to evaluate the long-term outcomes and optimize treatment strategies for this complex population.