Objective: Substance use disorders occur in as many as 50% of persons with schizophrenia at some point during their lifetime. Substance use is implicated in neuropsychological deficits among healthy controls; however, the literature has been varied with respect to persons with schizophrenia. Prevalence of negative symptoms, social functioning, and better premorbid functioning have been implicated as possible moderating variables in the relationship between schizophrenia, substance use, and ultimate neuropsychological profiles. This study aims to investigate the literature through meta-analysis in order to clarify these discrepancies. Data Selection: Online research databases were searched using the terms: schizophrenia, neuropsychological, substance use, and neurocognitive. From the available articles, only those directly comparing persons with schizophrenia with and without a history of substance use were used for the study. Effect sizes were computed for differences among neuropsychological indices consistent with the MATRICS cognitive domains, symptom domains, and demographic factors. Data Synthesis: Across multiple neuropsychological domains, people with schizophrenia alone were less impaired than with comorbid alcohol use disorders. This consistent trend for better performance without substance use disorder reverses for most domains assessed in comorbid cannabis use. Co-occurring cocaine use was associated with superior processing speed and poorer reasoning and problem-solving. Mixed substance use, however was substantively more varied. Conclusion: These findings go a long way toward elucidating the murky picture of neuropsychological deficits in schizophrenia and comorbid substance use disorders. Further, the comparative data between different classes of substances served provide important clinical information and considerations for neurocognitive functioning in this population.