Ketamine’s potential to enhance neuroplasticity and its therapeutic implications have gained significant interest in multiple mental disorders. This narrative review introduces a model describing ketamine’s biphasic action: an acute neurochemical disruption followed by a delayed phase of enhanced neuroplasticity. The delayed phase represents a “window of plasticity,” wherein interventions like psychotherapy, neuromodulation, or other augmentation therapies can be applied to achieve persisting changes. This biphasic model, supported by preclinical and clinical evidence, underscores ketamine’s rapid onset of antidepressant effects, along with enhanced synaptic plasticity in the prefrontal cortex and hippocampus. Understanding the dynamics of this biphasic mechanism is key to optimizing timing and type of therapeutic interventions, thereby supporting augmentation therapy strategies to maximize ketamine’s potential. By establishing a framework that links neuroplastic changes with therapeutic interventions, the model provides a scientifically grounded approach to achieving sustained clinical improvement initiated by ketamine in individuals with severe psychiatric disorders.