The learning process carried out is still teacher-centered in conventional ways such as lectures and the lack of use of learning materials or supporting learning devices. This study aims to test the effectiveness of scientifically-based E-LKPD in improving students' critical thinking skills and learning interest in the body's defense system material. This type of research is quasi-experimental with a pre-test design and post-test control group design. The research was conducted at Senior High School 2 Sleman. Limited trials were conducted in class XI MIPA 1 and field trials were carried out in class XI MIPA II as an experimental class and class XI MIPA II as a control class. The sampling technique is carried out by cluster random sampling. Data collection used several instruments, namely interviews, needs analysis questionnaires, assessment questionnaires for material experts, media expert assessment questionnaires, RPP expert assessment questionnaires, syllabus expert assessment questionnaires, biology teacher assessment questionnaires, student response questionnaires, learning interest questionnaires, critical thinking test sheets. Data analysis techniques use the normality test, homogeneity test, T-test, Mann-Whitney test, and n-gain score. The results obtained from this study revealed that the use of scientifically-based E-LKPD in the learning process is effective in improving the critical thinking skills and learning interests of students. Improving students' critical thinking skills is included in the high category with an n-gain value of 0.76 and interest in learning with an n-gain value of 0.75 is also included in the high category.