Abstract: Background: Olanzapine (OLZ), an atypical antipsychotic drug, causes weight gain and diabetogenic effects in a subset of patients. Conventional anti-diabetic drugs such as Metformin (MET) are often prescribed to reduce these effects. Recent evidence suggests that acetaminophen (APAP) may be an effective alternative to MET in patients receiving OLZ. The purpose of this study was to directly compare APAP, MET and APAP plus MET in the prevention of metabolic changes due to OLZ in C57BL/6J mice consuming a High Fat (HF) diet. Materials and Methods: Body weight gain, body fat percentage, glucose tolerance, plasma insulin levels, insulin resistance and glycosylated hemoglobin levels were measured and analyzed. Mice received a HF diet and tap water supplemented with OLZ (3 mg kg BW-1 d-1). Mice also received APAP (25 mg kg BW-1 d-1), MET (200 mg kg BW-1 d-1) or APAP+MET. Results: APAP significantly reduced fasting glucose levels by 30%. In OLZ-treated mice, MET reduced the total body fat percentage (17%), impaired glucose tolerance (64%), fasting blood glucose (14%), insulin resistance (26%) and glycosylated hemoglobin levels (42%). Combined treatment with APAP+MET was more effective than either treatment alone in reducing rate of body weight gain (29%), fasting blood glucose (40%) and insulin resistance (36%). However, APAP elevated chronic blood glucose levels by 25%, estimated as glycosylated hemoglobin. Conclusion: Overall, MET appeared to be the better drug in the prevention of OLZ-induced pre-diabetic changes than APAP. While treatment with APAP+MET may improve some pre-diabetic risk factors, concerns regarding the effect APAP on chronic levels of blood glucose may limit its clinical relevance.