Although English-medium instruction (EMI) has been implemented and developed rapidly in higher education, little is known about its learning process and effects. This study employed a systematic approach to explore how diverse factors affect student performance in English and disciplinary learning. We conducted a survey to collect students' self-report of their learning in the EMI programmes and used partial least square structural equation modelling in evaluation. The findings demonstrate three personal factors (prior knowledge, effort, and interest) and three environmental factors (course, teacher, and resource) have effects on student performance. We find that effort has the strongest direct impact on learning outcomes, prior knowledge the second, while course factor the least. Interest has an indirect effect on outcomes through the mediating effect of effort, and teacher and resource factors have indirect effects on outcomes mediated by course. In addition, prior knowledge has a larger impact on English performance than on subject achievement. The present study theoretically and methodologically contributes to the research field of EMI by systematically examining the learning process of EMI and constructing a structural model of complex relationships of multiple factors affecting student performance in EMI programmes. This study also provides implications for EMI practice.