Background: Nowadays, there is a paradigm shift in medical education. This shift occurred following the Covid-19 crisis. The world uses digital e-learning to support the public health response to this pandemic. The study's objective was to determine the medical students’ acceptance and perceptions of e-learning during the Covid-19 closure time in Jeddah. Methods: A cross-sectional, web-based study was done among 340 medical students from King Abdulaziz University, 2020. A standardized, electronic, self-administered, Google Form data collection sheet was distributed. It included the E-learning acceptance measure (ElAM) containing three constructs, namely: tutor quality (TQ), perceived usefulness (PU), and facilitating conditions (FC). The sheet also inquired about the students’ perceptions of the benefits, enablers, and barriers to e-learning. Descriptive, inferential statistics and multiple linear regression analyses were applied. Results: Blackboard and Zoom were the most preferred Learning Management Systems (LMS) by our medical students. The mean score of ElAM was 102.82 ± 24.102. Better achievers obtained significantly (P < 0.001) higher scores in all ElAM constructs. About three-fifths of the students confirmed that e-learning substituted classical on-campus learning and was an adaptable, and less time-consuming method. The educator's good e-learning skills, the subject, instructional design, interaction, motivation, and good LMS were agreed as enablers of e-learning. However, most students accepted that clinical teaching is the most challenging learning outcome and that exams could be affected by low internet quality. Conclusion: Medical students moderately accepted e-learning during the Covid-19 Pandemic closure time. More training of the students and tutors, better designing e-courses, more interaction, motivation, and blended learning are recommended.