ImportanceThe rise of fentanyl and other high-potency synthetic opioids across US and Canada has been associated with increasing hospitalizations and unprecedented overdose deaths. Hospitalization is a critical touchpoint to engage patients and offer life-saving opioid use disorder (OUD) care when admitted for OUD or other medical conditions.ObservationsClinical best practices include managing acute withdrawal and pain, initiating medication for OUD, integrating harm reduction principles and practices, addressing in-hospital substance use, and supporting hospital-to-community care transitions. Fentanyl complicates hospital OUD care. Fentanyl’s high potency intensifies pain, withdrawal, and cravings and increases the risk for overdose and other harms. Fentanyl’s unique pharmacology has rendered traditional techniques for managing opioid withdrawal and initiating buprenorphine and methadone inadequate for some patients, necessitating novel strategies. Further, co-use of opioids with stimulants drugs is common, and the opioid supply is unpredictable and can be contaminated with benzodiazepines, xylazine, and other substances. To address these challenges, clinicians are increasingly relying on emerging practices, such as low-dose buprenorphine initiation with opioid continuation, rapid methadone titration, and the use of alternative opioid agonists. Hospitals must also reconsider conventional approaches to in-hospital substance use and expand clinicians’ understanding and embrace of harm reduction, which is a philosophy and set of practical strategies that supports people who use drugs to be safer and healthier without judgment, coercion, or discrimination. Hospital-to-community care transitions should ensure uninterrupted access to OUD care after discharge, which requires special consideration and coordination. Finally, improving hospital-based addiction care requires dedicated infrastructure and expertise. Preparing hospitals across the US and Canada to deliver OUD best practices requires investments in clinical champions, staff education, leadership commitment, community partnerships, quality metrics, and financing.Conclusions and RelevanceThe findings of this review indicate that fentanyl creates increased urgency and new challenges for hospital OUD care. Hospital clinicians and systems have a central role in addressing the current drug crisis.