English-medium instruction (EMI) is rising in importance in higher education, especially for fields such as medicine. However, most students have some degree of linguistic barriers when studying courses in EMI. This study explored the challenges medical students face in studying medicine taught in English; whether these challenges differ by gender, academic discipline or academic level; and students’ perceptions of the relationship between English proficiency and academic performance in EMI. It drew upon cognitive load theory to explain how these linguistic difficulties influence students’ ability to manage the cognitive load of EMI in medical studies. The study included 264 Saudi EFL medical students who had nine years of prior English experience. The English-Medium Instruction Challenges Scale, adapted from Aizawa et al. (2020), measured perceived challenges in writing, speaking, reading, and listening. The participants’ International English Language Testing System (IELTS) scores represented their English language proficiency, their specialized-English competence was gauged through English for Specific Purposes (ESP) scores, and their grade point averages (GPA) represented academic success. A multivariate analysis of variance (MANOVA) showed significant differences in challenges according to discipline and academic year, and an analysis of variance (ANOVA) showed differences that were not significant with regard to gender. It was found in the regression analysis that students with lower English proficiency (IELTS scores) reported more language challenges in EMI contexts. However, ESP scores did not significantly affect perceived challenges, becoming insignificant once IELTS scores were obtained. This study emphasises the need for language training to be incorporated into medical EMI settings and calls for policy reforms to include EMP to empower future health care professionals with the needed language skills that clinical settings require.