Higher education worldwide has witnessed a rapid growth of English-as-a-medium-of-instruction (EMI) courses. Research reported complex challenges teachers encounter in transitioning from using L1 as a medium-of-instruction to EMI and acknowledged the importance of teachers’ agency and perceptions. However, little is known about how teachers exercise agency to act on demands of EMI teaching and the role their perceptions play in this process. Within EMI research, teacher agency is not always systematically theorised. Adopting a cultural-historical theory perspective, this study explores how Vietnamese EMI teachers exercise agency to act on perceived demands of teaching academic subjects in English. Data included in-depth individual interviews with 15 EMI teachers from ten universities in Vietnam. Findings revealed these teachers exercised their agency in response to what they perceived as meaningful and important within the broader societal conditions for EMI and the particular activity settings of their discipline with specific EMI student cohorts. They exercised agency to transform EMI practice to be learner-centred, critical thinking- and content knowledge-focused, and future/outcome-oriented, and through this process also transformed themselves as EMI teachers. Findings have implications for EMI research and practice, and for supporting institutions and teachers embarking on EMI.