Although English used as a medium of instruction (EMI) has gained much research attention recently, there is still a dearth of studies that look into the differences and contrasts as construed by learners with different academic backgrounds. This study thus aims to investigate how students with different academic backgrounds (natural sciences versus social sciences) verbalize their attitude towards EMI and which challenges they face at a Vietnamese higher education institution. Two hundred and five questionnaires, accompanied with ten semi-structured interviews were used to obtain relevant research data. The results showed that the students in natural sciences (NS) and social sciences (SS) had generally accepted and embraced EMI as an essential part of their university education. However, some significant attitudinal differences were found between students studying NS and SS in terms of their belief (cognitive aspect), their perceived benefits (affective aspect), and their intentions and strategies (behavioral aspect) towards EMI. It was also noticed that the students encountered a variety of challenges in EMI. Finally, some implications will be drawn from the findings with an aim to enhance the quality of EMI delivery at tertiary level.