Fever is a common manifestation of both infectious and noninfectious processes in recipients of hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy. Understanding the diverse causes of fever in these settings allows for accurate diagnosis and optimal use of antibiotics. Herein we review common noninfectious syndromes seen in HCT and CAR-T recipients and discuss best practices in the management of these complex clinical scenarios regarding diagnosis and antibiotic use. In recent years, adverse effects of antimicrobials have highlighted the importance of antimicrobial stewardship in HCT and CAR-T patients, and an antibiotic de-escalation strategy is a safe and important tool in mitigating these adverse events, even in patients with ongoing neutropenia who become afebrile without a known infection. Common adverse events associated with antibiotics include an increased risk of Clostridiodes difficile infection (CDI), a higher incidence of multidrug-resistant organisms (MDROs), and microbiome dysbiosis. Clinicians should be aware of noninfectious causes of fever in these immunocompromised patients and utilize best antibiotic practices while managing these patients.