Many universities and colleges in developing countries around the world have started using e-learning courses to keep up with the technological revolution of the higher education sector in the developed world. E-learning has served as a catalyst for higher education to expand in the last decade. However, there are still many challenges facing universities in the developing world, as they attempt to implement e-learning. This paper investigated the main challenges that could significantly impact the implementation of e-learning in developing countries. The main objective of this paper was to identify these challenges and examine how they are related to the challenges facing instructors when using e-learning systems. A total of 107 university instructors responded to an online questionnaire about their perceptions of the main challenges in implementing e-learning in a university context. A partial least squares structural equation model (PLS-SEM) was employed to test the relationships between certain course, contextual, technological, and individual challenges. Challenges related to the design of the course, the support provided, societal/culture, and technology were found to have a significant impact on the instructors' use of e-learning systems. Several implications for the policymakers and practitioners were discussed. INDEX TERMS E-learning, higher education, individual challenges, technology utilization.