E-learning anxiety plays a key role in students' success in online courses. One of the factors that may affect students' e-learning anxiety is computer self-efficacy (CSE). However, the role of CSE in high school students' e-learning anxiety has remained unexplored in the Iranian context. Therefore, the present mixed-methods study purports to explore the role of CSE in Iranian high school students' e-learning anxiety. To this end, for the quantitative part, 410 female high school students were selected, as well as for the qualitative part, 30 female high school students were selected using a random sampling method. The required data were collected using a computer self-efficacy questionnaire, an anxiety in online classes questionnaire, and semi-structured interviews. The collected data were analyzed through a Pearson correlation analysis, a multiple-regression analysis, and a content analysis. Results revealed a strong negative correlation between the students' CSE and e-learning anxiety. Further, the findings documented that the factors of CSE (i.e., beginning skills, mainframe skills, and advanced skills) determined the high school students' e-learning anxiety. Moreover, the complementary qualitative findings yielded four overarching themes: 'promoted digital literacy', 'increased problem-solving', 'increased learning satisfaction', and 'enhanced self-regulated learning'. Finally, a range of implications is suggested for different stakeholders.