The study examined the efficacy of the Bioecological Model of Human Development to predict Ghanaian primary school pupils' academic achievement in a National Education Assessment test in English language and mathematics. A total of 19,458 primary 3 and 17,447 primary 6 pupils from 548 schools were involved in the study. Participating schools were selected using stratified random sampling. Using a hierarchical multiple regression with a significance criterion at p < 0.001, pupils' academic achievement was found to be significantly influenced by their personal characteristics, as well as the micro and macro environments they interacted in. Consistent with the theoretical model, pupils' microsystems contributed most to their levels of academic achievement. Moreover, the impact of pupils' personal characteristics on their academic achievement was moderated by the types of micro and macro systems they operated in. The outcome of the study validates the model's proposition that none of the variables operates in isolation but are mutually dependent in determining the levels of pupils' academic achievement in a given context. It is therefore suggested curriculum developers and education policy formulators to be guided by the model in attempts to initiate interventions to address the problem of low academic achievement among primary school pupils' in Ghana.