The COVID-19 pandemic created the need for rapid and urgent guidance for clinicians to manage COVID-19 among patients and prevent transmission. To appraise the quality of clinical practice guidelines (CPGs) using the National Academy of Medicine (NAM) criteria. A search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials to December 14, 2020, and a search of related articles to February 28, 2021, that included CPGs developed by societies or by government or nongovernment organizations that reported pharmacologic treatments of hospitalized patients with COVID-19. Teams of 2 reviewers independently abstracted data and assessed CPG quality using the 15-item National Guideline Clearinghouse Extent of Adherence to Trustworthy Standards (NEATS) instrument. Thirty-two CPGs were included in the review. Of these, 25 (78.1%) were developed by professional societies and emanated from a single World Health Organization (WHO) region. Overall, the CPGs were of low quality. Only 7 CPGs (21.9%) reported funding sources, and 12 (37.5%) reported conflicts of interest. Only 5 CPGs (15.6%) included a methodologist, described a search strategy or study selection process, or synthesized the evidence. Although 14 CPGs (43.8%) made recommendations or suggestions for or against treatments, they infrequently rated confidence in the quality of the evidence (6 of 32 18.8%), described potential benefits and harms (6 of 32 18.8%), or graded the strength of the recommendations (5 of 32 15.6%). External review, patient or public perspectives, or a process for updating were rare. High-quality CPGs included a methodologist and multidisciplinary collaborations involving investigators from 2 or more WHO regions. In this review, few COVID-19 CPGs met NAM standards for trustworthy guidelines. Approaches that prioritize engagement of a methodologist and multidisciplinary collaborators from at least 2 WHO regions may lead to the production of fewer, high-quality CPGs that are poised for updates as new evidence emerges. PROSPERO Identifier: CRD42021245239.