Ketamine, often associated with its frequent illicit recreational use, is renowned as an approved alternative for treatment-resistant depression. This paper evaluates the mechanism of ketamine’s role in treating depression, emphasising its positive safety profile and acute onset of action. Ketamine’s mechanism of action involves antagonism of N-methyl-D-Aspartate (NMDA) receptors, leading to increased glutamate production in brain regions associated with mood regulation. Moreover, ketamine counteracts the effects of chronic stress by promoting synaptic plasticity and neurogenesis. However, the response to ketamine varies among individuals, prompting the need for further investigation into the factors influencing its efficacy, such as route of administration, dose and the rate at which it is delivered. Other variables such as past traumatic experiences and genetic predispositions may also play a significant role in determining an individual’s response to ketamine therapy, raising the importance of tailored treatment approaches. Furthermore, there is growing interest in investigating the synergy of ketamine alongside other therapeutic modalities, including Cognitive Behavioural Therapy (CBT) and Mindfulness-Based Interventions (MBIs), as a means to enhance treatment outcomes in modern psychiatry.