This case report describes the clinical response and safety of intranasal esketamine (Spravato®) in a 61-year-old female with treatment-resistant depression (TRD), a history of electroconvulsive therapy (ECT) poor response, and structural brain abnormalities secondary to left frontal lobe tissue loss from traumatic brain injury in 2008. Despite multiple antidepressant trials, atypical antipsychotic augmentation, and 6 ECT sessions since 2019, the patient achieved only partial remission. In 2024, she received four 56 mg doses of Spravato over 2 weeks while maintaining duloxetine, fluvoxamine, and clozapine therapy. Montgomery-Åsberg Depression Rating Scale (MADRS) scores improved from severe to mild depression, with resolution of suicidal ideation and symptom stabilization. Anxiety symptoms decreased and nightmares ceased post-treatment. Transient dizziness occurred approximately 10 minutes post-administration in all sessions, resolving with 90 minutes of bed rest. No severe adverse events (dissociation, psychosis, or hypertensive crises) were observed. Although limited by an abbreviated treatment regimen and a single-case design, this case suggests that esketamine may be considered in carefully selected TRD patients with structural brain abnormalities and prior ECT poor response, pending validation from larger studies.