In recent years, reading comprehension studies have followed a componential approach aimed at determining the way in which variables interact. However, in L2 academic reading comprehension, this progress is still in its initial stages. With this context in mind, this paper aims to explore the relationship between prior knowledge and L2 reading comprehension by proposing a mediation model that considers L2 vocabulary knowledge and metacognitive awareness as mediating variables. A final sample of 75 Chilean university students with an intermediate level of English was used for the study. The variables measured were prior knowledge, vocabulary breadth, metacognitive awareness of reading strategies, and reading comprehension. Among the findings of this study, we propose a simple mediation model in which vocabulary knowledge functions as a mediator between prior knowledge and reading comprehension. Unexpectedly, the impact of metacognitive awareness was not found to be statistically significant.