Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that affects approximately 2% of the human population. Traditional treatment of OCD includes selective serotonin reuptake inhibitor (SSRI) or serotonin reuptake inhibitor (SRI) treatment along with cognitive behavioral therapy (CBT). Nearly 25%-30% of OCD patients do not respond to SSRIs. Glutamatergic agents are currently being studied for the treatment of OCD due to the glutamatergic pathway in the brain, related to OCD, and the role of the cortico-striato-thalamic circuit (CSTC). This review assesses the clinical effectiveness of N-methyl-D-aspartate (NMDA) antagonists, ketamine/esketamine, memantine, and amantadine, for adult patients with OCD. Inclusion criteria include human studies published within the last 15 years, with patients diagnosed with OCD, aged over 18 years, with only psychiatric comorbidities, and full-text articles. Papers that included interventions other than CBT, exposure with response prevention (ERP), and SSRI/SRI were excluded. Articles were searched for using PubMed, PubMed Central, Medical Literature Analysis and Retrieval System Online, GeorgiA LIbrary LEarning Online, EBSCO Information Services, OpenAthens, Multidisciplinary Digital Publishing Institute, and Google Scholar databases, last searched on December 2, 2022. The risk of bias was assessed using Cochrane Risk of Bias tools, the Scale for the Assessment of Narrative Review Articles (SANRA) checklist for literature reviews, and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for quasi-experimental studies. Results were presented and synthesized by Excel spreadsheet analysis. The database search yielded 4,221 articles, which was cut down to 18 articles by inclusion/exclusion criteria, including duplications. 80% of the ketamine studies resulted in a significant reduction of obsessions and compulsions based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and each of the memantine and amantadine studies displayed clinical effectiveness, also. Limitations include the small number of amantadine studies and the limited availability of other NMDA receptor (NMDAR) antagonist-focused studies. This systematic review shows that ketamine is an effective drug for the treatment of non-refractory, mild to moderate OCD, and memantine and amantadine are effective augmentation agents for the treatment of mild to severe OCD.