Objective: To determine the efficacy and safety of second-generation antipsychotics (SGAs) as adjunctive analgesics. Data Sources: A comprehensive literature review was conducted between August 2020 and January 2021 on PubMed, Scopus, and ProQuest Central. Study Selection and Data Extraction: Keyword and Boolean phrase searches using the following terminology were conducted: “Quetiapine” OR “Risperidone” OR “Olanzapine” OR “Ziprasidone” AND “Analgesia” NOT “Psychosis” NOT “Psych.” Articles that involved human adult patients who received any of the SGAs mentioned in the searching filter with an opioid were included. Articles that described pediatrics, pregnant women, patients who received any of these agents for treatment of psychosis and articles that were not in English, or readily translatable to English, were excluded. Data Synthesis: Three articles were selected for inclusion in this review, with 2 articles detailing reports with olanzapine and 1 article describing a randomized, controlled trial with extended-release quetiapine. Both olanzapine and quetiapine were able to decrease pain scores on the numeric rating scale, indicating a reduction pain experienced, and additionally reduced opioid craving behavior in patients. Depression scores and quality-of-life indicators improved with quetiapine, though those metrics were not studied with olanzapine. Conclusions: Select SGAs, specifically extended-release quetiapine and olanzapine, may serve as an appropriate adjunctive analgesic choice in select patients. Further research is required in a clinical setting to determine the exact role of this drug class in pain management.