Significance Rhinovirus (RV) is the causative agent of the common cold and other respiratory tract infections. Despite the vast prevalence, effective treatment or prevention strategies are lacking. Here, we analyzed metabolic alterations in infected cells and found a pronounced reprogramming of host cell metabolism toward an anabolic state, which involved enhancement of glucose uptake and glycogenolysis. We further demonstrate that these alterations can be reverted by treatment with 2-deoxyglucose, a glycolysis inhibitor, which results in a disruption of RV replication in vitro and in vivo. Thus, we show how the specific metabolic fingerprint of viral infection can be used to generate targets for antiviral therapy.