Background: Neutropenia and febrile neutropenia (FN) are serious complications of myelosuppressive chemotherapy and present a considerable burden to patients with cancer. Febrile neutropenia is associated with increased risks of infection and hospitalization, a particular concern during the coronavirus disease 2019 (COVID-19) pandemic. Oncology nurses and advanced practice providers (APPs; including nurse practitioners, physician assistants, advanced practice nurses, and pharmacists) play a vital role in the management of patients with cancer and the prevention of infections. Objectives: The objectives of this article are to summarize the burden of chemotherapy-related neutropenia and FN in patients with cancer in the US and to evaluate the role of oncology nurses and APPs in preventing and managing FN. Methods: This article provides a narrative review of US studies reporting on the burden of FN, FN during COVID-19, adherence to guidelines for the use of prophylactic granulocyte colony-stimulating factors (G-CSFs), the involvement of oncology nurses in FN prevention, management, and patient quality of life, and inappropriate and/or incomplete G-CSF treatment. Findings: Despite advances in supportive care for patients with cancer receiving myelosuppressive chemotherapy, neutropenia and FN present a considerable burden to patients, particularly during the COVID-19 pandemic. Oncology nurses and APPs play a vital role in the appropriate and timely delivery of supportive care, which can improve patient outcomes and minimize treatment costs.