This mixed-methods study explores the relationship between early elementary students' domain-specific vocabulary knowledge and their ability to comprehend grade-level reading passages on unfamiliar science topics. Specifically, this study used (a) structural equation modeling (SEM) to examine the extent to which students' networks of domain-specific vocabulary knowledge in Grades 1 and 2 mediated the effects of a Tier 1 content-based literacy intervention on domain-specific reading comprehension scores in Grade 2 (N = 2,156); and (b) quantitative survey and qualitative interview data from teachers (N = 48) to surface new themes about teacher vocabulary instruction that might suggest potential explanations for the SEM findings. SEM analysis revealed that students' domain-specific vocabulary knowledge in first and second grade explained 69% of the treatment effect on a domain-specific reading comprehension outcome. Results from the quantitative survey also indicated that treatment group teachers reported providing more incidental exposures to vocabulary than control teachers (effect size = 0.54), and qualitative analyses revealed that teachers with high incidental exposures tended to provide expanded opportunities for their students to engage with words and to connect words to topics. Findings from this mixed-method study paint a more complete picture of (a) the important role domain-specific vocabulary knowledge plays in facilitating reading comprehension transfer in the domain of science, and (b) what teachers do during vocabulary instruction to promote transfer in domain-specific reading comprehension.