The present study aims to advance the extant research base by evaluating the implementation and effectiveness of an academic vocabulary program designed for use in mainstream middle school classrooms with high proportions of language minority learners. The quasi-experimental, mixed-methods study was conducted in 21 classes (13 treatment matched to 8 control) in seven middle schools in a large district, with 476 sixth-grade students (346 language minority learners, 130 native English speakers). Classroom observations and teacher logs indicated the 18-week program was implemented with good fidelity and that the approach contrasted sharply with the standard district English language arts (ELA) curriculum. Multilevel modeling indicated that the program resulted in significant effects on several aspects of vocabulary knowledge, including meanings of taught words (d = 0.39; p less than 0.0001), morphological awareness (d = 0.20; p = 0.0003), and the word meanings as presented in expository text (d = 0.20; p = 0.0227). The program also yielded marginally significant, but promising effects on a depth of word knowledge measure (d = 0.15; p = 0.0830) and a norm-referenced measure of reading comprehension (d = 0.15; p = 0.0568). No effects were found on a norm-referenced vocabulary measure. These effects were comparable for language minority learners and their native-English-speaking classmates. Data from teachers shed light on the challenges of meeting students' diverse instructional needs and the roles of curriculum and professional networks in building instructional capacity. The findings show promise in developing effective multifaceted vocabulary instruction for implementation by ELA teachers in middle school classrooms with high numbers of language minority learners.