The COVID-19 pandemic has rapidly accelerated the adoption of e-learning across educational institutions worldwide, especially in health professions education. This study explored the factors influencing e-learning acceptance among health professions students and faculty members in Iran using an extended Technology Acceptance Model (TAM). A descriptive cross-sectional study was conducted among 932 participants, including faculty members, postgraduates, and undergraduates at Mashhad University of Medical Sciences, one of the top five universities in Iran. Data were collected through an online survey from August 1 to August 31, 2020. The TAM was extended by incorporating innovation, social, and organizational characteristics. Partial least squares structural equation modeling was used to analyze the relationships between constructs, including perceived ease of use (PEU), perceived usefulness (PU), and intention to use e-learning. The findings revealed that PEU and PU were pivotal in shaping e-learning acceptance, underscoring the need for user-friendly and effective platforms. Attitude toward e-learning significantly influenced participants' intention to use e-learning platforms, with PEU emerging as the most influential factor. PU had a more substantial impact on faculty members and undergraduate students, while postgraduates placed less emphasis on usefulness. Organizational factors only indirectly affected e-learning acceptance, mediated by individual characteristics. This study underscores the importance of usability, technological infrastructure, and digital literacy training in promoting e-learning acceptance among health professions students and faculty members. These findings significantly impact policymakers, educators, and administrators in designing more user-centered e-learning platforms. Future research should explore the longitudinal effects of technological advancements and institutional policies on e-learning adoption.