Influenza is a significant problem within hospitals, leading to extended hospital stays, excess morbidity and mortality, and economic loss. Prevention and control strategies are generally “bundled”; therefore, the individual effects of particular strategies and the value of combined strategies cannot be determined directly, making it difficult to discern the optimal strategy. To quantify the individual and joint effectiveness of several known influenza infection control measures used in general hospitals, we simulated influenza transmission at a hypothetical hospital in Ann Arbor, Michigan, during a 1-year seasonal epidemic (June 2012–June 2013), using a susceptible-exposed-infected-recovered (SEIR) compartmental model. The hospital population comprised patients and health-care workers, interacting with its larger community population. Parameter ranges and values were determined from the literature (both national and local to Ann Arbor) and took into account coverage levels and effects of vaccination. The most effective individual strategies, based on percent reduction of cases, were: hand-washing (11%–27%), health-care worker vaccination (6%–19%), prevaccination of patients (4%–17%), patient isolation (5%–16%), antiviral treatment (4%–14%), and use of face masks (3%–10%). Use of all strategies together with ideal levels of compliance could potentially halve the number of observed hospital cases of influenza; under a more realistic scenario, an almost 40% reduction could be achieved. A multifaceted approach is imperative to control and prevent nosocomial influenza in health-care settings.