Treatment-resistant depression (TRD) represents one of the most severe forms of major depressive disorder and is associated with high morbidity and mortality, functional impairment, increased suicidal ideation, and significant socioeconomic impacts. In this context, ketamine and esketamine have emerged as innovative therapeutic alternatives due to their rapid antidepressant effect and their potential to reduce suicidal ideation within a few hours of administration. The aim of this study was to critically analyze the available scientific evidence regarding the therapeutic use of ketamine and esketamine in treatment-resistant depression, emphasizing their clinical efficacy, mechanisms of action, safety profile, and future prospects. A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. Searches were conducted in the PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library, and PsycINFO databases, using search terms related to treatment-resistant depression, ketamine, esketamine, NMDA receptors, neuroplasticity, and suicidal ideation. After applying the eligibility criteria, 92 studies were included for qualitative analysis. The evidence demonstrated that both intravenous ketamine and intranasal esketamine promote a rapid and significant reduction in depressive symptoms and suicidal ideation, especially in patients with multiple treatment failures. The mechanisms of action involve modulation of glutamatergic neurotransmission, activation of AMPA receptors, increased expression of brain-derived neurotrophic factor (BDNF), and restoration of brain neuroplasticity. The main adverse events were transient dissociative symptoms, temporary elevation of blood pressure, nausea, and dizziness, presenting a favorable safety profile when used under specialized monitoring. It is concluded that ketamine and esketamine represent important therapeutic advances in the treatment of treatment-resistant depression, particularly due to the rapid clinical response and the potential to reduce the risk of suicide. However, further studies are needed to define optimal maintenance protocols, assess long-term safety, and expand the use of these therapies in evidence-based clinical practice.