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Flipped instruction—the replacement of traditional in-class lecture with at-home, multimedia instruction—has grown increasingly common in schools. However, the existing evidence to support its effectiveness in K-12 science classrooms lacks substantial quantitative data to warrant such an enthusiastic embrace. This quasi-experimental mixed-methods study compared learning outcomes in high school Biology students who experienced a flipped lesson to those of peers who experienced a control, traditional lecture-based lesson on the same topic. Average gains from pre-test to post-test were significantly higher for flipped students. Flipped students' completion of homework was particularly important in this effect. Interview data suggest that the multimedia nature of the homework, as well as its convenience, contributed the significant gains of flipped students.