Substance use disorders (SUDs), including alcohol, opioid, and cocaine dependencies, present significant challenges in public health. Current treatment modalities often face limitations in efficacy and accessibility, necessitating exploration of novel therapeutic approaches. Ketamine, originally recognized for its anesthetic properties, has garnered attention for its potential in treating SUDs due to its unique pharmacological actions. This chapter synthesizes current literature on the use of ketamine in alcohol, opioid, and cocaine use disorders, highlighting its mechanisms of action, clinical effectiveness, and safety profile. Through its N-methyl-D-aspartate receptor antagonism and rapid-acting antidepressant effects, ketamine offers promise in reducing cravings, withdrawal symptoms, and relapse rates in clinical study of SUDs. Ketamine’s ability to modulate glutamatergic transmission and promote neural plasticity may contribute to the therapeutic effects in addiction. Challenges such as optimal dosing, long-term safety, and potential for abuse require further investigation. This chapter underscores the evolving landscape of ketamine as a potential adjunctive therapy in SUDs, emphasizing the need for rigorous clinical trials to establish its place in addiction treatment protocols.