<p>Recently, engineering design-based science instruction has gained ongoing attention in K-12 education. Based on literature readings, researchers have shown considerable interest in two engineering design models used in science education. One engineering design model came from the National Science Foundation project in the United States, called the Teachers and Researchers Advancing Integrated Lessons in STEM (science, technology, engineering, and mathematics) (TRAILS), abbreviated as EDMT; the other came from a researcher whose last name is Li, abbreviated as EDML. These two engineering design models were used in the same science course called “Epidemic Prevention Access Control”, aiming to improve students’ STEM competence and analyze their engineering design behaviors. A pretest-posttest nonequivalent group design was conducted with 63 public high school students in 12 lessons. Quantitative data were collected through a STEM knowledge test, students’ artifacts, and a STEM attitude scale, while qualitative data were collected through reflective practices. Repeated measures analysis of variance (ANOVA) showed that, compared to EDML, EDMT significantly enhanced high school students’ STEM competence (STEM knowledge, hands-on skills, and STEM attitude). Lagged sequence analysis indicated that students in the EDMT group had more significant engineering design behaviors. These provide a reference for high school teachers, encouraging them to choose appropriate engineering design models for interdisciplinary teaching.</p>