The immediate shift to remote teaching or distance learning, due to COVID-19 management strategies, most notably limited in-person contact, was abruptly implemented in universities worldwide. This process was demanding for both the instructors and the students, notwithstanding. The present study examined the challenges in a course attributed as the most challenging during the COVID-19 pandemic by health sciences students of different socio-demographic backgrounds, life circumstances, educational background and academic achievement (N = 743). A questionnaire was designed and translated to French employing the forward-backward translation method. The factor structure and reliability were examined by Categorical Principal Component Analysis (CATPCA) and Cronbach's alpha, respectively. Chi-square tests with post-hoc examinations using adjusted standardized residuals and z-tests of independent proportions were performed to investigate the group differences. Participants were bachelor and master students of Medicine, Pharmacy, Biomedicine, Physiotherapy, Public Health, Motor Sciences (Physical Education) and Dentistry from the University of Liege, Belgium. Results revealed that the most three reported challenges were difficult learning content, course intensity, feeling of stress and worry. Additionally, online learning implementation due to Covid-19 measures, feeling of failure (not having learnt what was supposed to be learnt) and lack of instructors' interaction and support were mentioned as the prominent challenges encountered. Furthermore, more bachelor, full-time and female students, students who were in early stages of the learning trajectory and low and averaged achievers reported experiencing challenges with difficult learning content, course intensity, stress and online learning. The findings, thus, emphasized the role of faculty-led and instructors' support in the early stages of students' learning trajectory and adequate attention to their well-being if online learning is to be institutionalized.