This study reports on a conceptual model that provides insight into the relationship between English reading proficiency and academic performance of first-year science and mathematics university students in Ghana, and an empirical test of that model. Longitudinal data were acquired from a sample of 133 students. Using three different mediation analyses, the study demonstrated significant medium-sized effects of English reading proficiency on students' grade point average (GPA) by the end of year 1 and a small but significant indirect relationship between reading proficiency and the final GPA scores by the end of year 4, mediated by the GPA scores after year 1. These findings show that the academic English reading proficiency of students in a non-western multilingual academic context is important for their academic achievement. It also found that academic results obtained by students in their first-year at University were a sound predictor for success at the end of their studies. Results from this study confirm the need for universities in multilingual settings to invest in L2 students' English reading proficiency at the start of their academic programs. Instructional recommendations are made, along with suggestions for further study.