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Background/Objectives: Intranasal esketamine has emerged as an effective treatment for patients with treatment-resistant depression (TRD), providing rapid symptom relief when conventional antidepressant strategies fail. While its pharmacological efficacy has been demonstrated in randomized controlled trials, less attention has been paid to the organizational, relational, and multidisciplinary aspects that influence its real-world implementation and clinical effectiveness. While practical recommendations for intranasal esketamine services exist, an implementation-ready framework integrating psychiatry, nursing, and psychotherapy across treatment phases is still lacking. This narrative review synthesizes the clinical and real-world evidence and proposes a phase-based integration framework with explicit role delineation and measurable implementation/fidelity indicators. Methods: We conducted a narrative review informed by a structured literature search in major databases from inception to the most recent update. Search terms combined 'esketamine'/'Spravato' with 'treatment-resistant depression', 'nursing', 'psychotherapy', 'multidisciplinary', and 'implementation'. Outcomes prioritized in the synthesis included depressive symptom severity/response, relapse prevention, safety/tolerability, anhedonia, suicidality monitoring, functional outcomes, and patient-reported experience/retention. Based on this evidence, an integrated, phase-based multidisciplinary framework for esketamine treatment was developed. Results: Available evidence supports the efficacy of intranasal esketamine in reducing depressive symptoms in TRD, with growing real-world data confirming its effectiveness and safety. Beyond global symptom improvement, studies highlight benefits on clinically relevant domains such as anhedonia and suicidality trajectories, as well as meaningful patient-reported outcomes. However, the complexity of esketamine delivery requires structured clinical pathways. The proposed model delineates complementary roles for medical supervision, nursing care, and psychotherapy across pre-treatment assessment, induction and session delivery, post-session integration, and maintenance phases, emphasizing safety, continuity of care, and patient-centred monitoring. Conclusions: Intranasal esketamine represents not only a pharmacological innovation but also a treatment that necessitates an integrated multidisciplinary approach. A structured phase-based multidisciplinary approach may support safer, more acceptable delivery of intranasal esketamine and potentially improve retention and patient experience; however, prospective implementation and comparative studies are needed to evaluate clinical effectiveness, feasibility, and cost-effectiveness.