<b><i>Introduction:</i></b> Trastuzumab deruxtecan is a monoclonal antibody linked to a chemotherapy moiety that was recently approved by the Food and Drug Administration (FDA) for the treatment of metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancers. There are labeled black box warnings for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity. Additionally, chemotherapy-induced nausea and vomiting (CINV) was reported to be as high as 78% (∼8% grade 3 or higher) in phase I and II clinical trials. Clinical trial and package insert recommendations for the management of CINV are not available, making real-world management difficult. <b><i>Case Presentation:</i></b> We reviewed the first 10 patients who received trastuzumab deruxtecan at our hospital-based community cancer center to determine if CINV management was adequate. We found a rate of 28.9% CINV (all grade 1 and 2) despite treatment as a moderate emetic potential regimen. Interventions by the treatment team to manage trastuzumab deruxtecan as a high-risk emetic regimen resulted in reduced CINV and ongoing treatment for all patients. <b><i>Discussion and Conclusion:</i></b> This review indicates that management of CINV for patients receiving trastuzumab deruxtecan should follow recommendations for regimens with a high-risk emetic potential.