Influenza A virus (IAV) remains a global health concern despite the availability of a seasonal vaccine. It is difficult to predict which strains will circulate during influenza season, and therefore extremely challenging to test novel vaccines in the human population. To overcome this obstacle, new vaccines must be tested in challenge studies. This approach poses significant safety problems, as current pharmacological interventions for IAV are poorly efficacious. New methods are needed to enhance the safety of these challenge studies. Here, we generate a virus expressing a small molecule-assisted shutoff (SMASh) tag as a safety switch for IAV replication. Addition of the SMASh tag to an essential IAV protein allows for small molecule-mediated inhibition of replication. Treatment with this drug controls SMASh-tagged virus replication in vitro and in vivo This model for restriction of viral replication has potential for broad applications in vaccine studies, virotherapy, and basic virus research.Importance Influenza A virus (IAV) causes significant morbidity and mortality worldwide annually, despite the availability of new formulations of the vaccine each season. There is a critical need to develop more efficacious vaccines. However, testing novel vaccines in the human population in controlled studies is difficult due to the limited availability and efficacy of intervention strategies should the vaccine fail. There are also significant safety concerns for work with highly pathogenic IAV strains in the laboratory. Therefore, novel strategies are needed to improve the safety of vaccine studies and highly pathogenic IAV research. Here we developed an IAV strain engineered to contain a small molecule-mediated safety switch. This tag, when attached to an essential viral protein, allows for regulation of IAV replication in vitro and in vivo This strategy provides a platform for regulation of virus replication without targeting viral proteins directly.