The integration of digital technology into healthcare is critical for health communication. This study analyzed a group of nursing students who applied multimedia health education e-books to different groups of varying sizes to explore the efficiency of implementing health communication and nursing information literacy in the nursing industry. If medical personnel can make appropriate use of technology, combine medical operations with information systems, and disseminate the purpose of health to groups of different sizes properly, the quality of patient care will improve. Thirty-two junior nursing students at the college level were divided into three groups, each subject to a 3-week internship. After the internship, a questionnaire survey was conducted. Additionally, nine nursing students were interviewed in a 45-min semistructured format. Regarding the effectiveness of nursing students using multimedia e-books to implement health communication and the development of nursing information literacy, the statistical analysis results demonstrated no significant differences between large groups and small groups. However, their 5-point Likert scale average values were all greater than 4, indicating that regardless of group size, their feedback on using e-books was positive. This means multimedia e-books can effectively help nursing students practice health communication application effectiveness and develop nursing information literacy.