Molnupiravir, a prodrug known for its broad antiviral activity, has demonstrated efficacy in animal models of COVID-19, prompting clinical trials, in which initial results indicated a significant effect against the disease. However, subsequent clinical studies did not confirm these findings, leading to the refusal of molnupiravir for permanent market authorization in many countries. This report critically assessed 22 studies published in 18 reports that investigated the efficacy of molnupiravir in animal models of COVID-19, with the purpose of determining how well the design of these models informed human studies. We found that the administered doses of molnupiravir in most studies involving animal COVID-19 models were disproportionately higher than the dose recommended for human use. Specifically, when adjusted for body surface area, over half of the doses of molnupiravir used in the animal studies exceeded twice the human dose. Direct comparison of reported drug exposure across species after oral administration of molnupiravir indicated that the antiviral efficacy of the dose recommended for human use was underestimated in some animal models and overestimated in others. Frequently, molnupiravir was given prophylactically or shortly after SARS-CoV-2 inoculation in these models, in contrast to clinical trials where such timing is not consistently achieved. Furthermore, the recommended five-day treatment duration for humans was exceeded in several animal studies. Collectively, we suggest that design elements in the animal studies under examination contributed to a preference favoring molnupiravir, and thus inflated expectations for its efficacy against COVID-19. Addressing these elements may offer strategies to enhance the clinical efficacy of molnupiravir for the treatment of COVID-19. Such strategies include dose increment, early treatment initiation, administration by inhalation, and use of the drug in antiviral combination therapy.