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Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans., Author Summary Respiratory syncytial virus is a major cause of chronic lung damage, asthma exacerbations, and hospitalizations of infants, elders, and high-risk adults. Currently, there is no effective vaccine or treatment available to protect the general population from RSV infection. Here, we demonstrate that defective forms of RSV genomes naturally generated during infection effectively stimulate the antiviral response in vitro and in vivo. In human cells, RSV iDVGs trigger the antiviral response through a mechanism characterized by the potent activation of the transcription factor IRF1 and a dominant expression of the type III IFN gene IFNL1 (IFN-λ1). This study establishes for the first time that naturally occurring iDVGs trigger robust host antiviral responses to RSV in mice and humans and reveals new opportunities to potentiate the host response to RSV infection and minimize viral-induced pathology.