Critical thinking (CT) is one of the desirable skills to be taught in school. It is not only considered an important 21st century skill for living in a democratic society, but also important for a deep understanding of domain-specific content. Despite its importance, studies show that students often lack the ability to think critically. Moreover, there is a lack of clear theory, supported by empirical findings, for developing domain-specific teaching-learning sequences to promote students’ CT. This makes teaching CT challenging for teachers. To address this gap, the presented study has two goals: to identify design principles for instruction that promotes critical thinking and to develop an exemplary instructional unit in particle physics on this basis. Particle physics is chosen because of its abstractness and complexity, as well as student interest in the subject. Another basis is a definition of CT that can be readily applied in the context of teaching physics. For this purpose, Halpern’s classification of CT strategies and their measurable outcomes is used. Furthermore, a distinction is made between general CT skills that provide a framework for CT, such as understanding the need to define terms precisely, and domain-specific CT skills that represent the application of general CT skills in a specific domain and require domain-specific expertise, such as distinguishing between the concepts of mass and matter in the context of particle physics. This study examines the development of both general and domain-specific CT. The teaching-learning sequences about antimatter (10 to 12 lessons) are developed for students in grades 10, 11, and 12 using the Design-Based Research (DBR) approach. Analysis of the data from pilot studies provides guidance for further development of the antimatter course and the creation of a teacher package that supports teachers both methodologically and in terms of content when implementing the antimatter course. In the main study, the course is implemented in 3 classes in different federal states of Germany. To evaluate the effectiveness of the course in promoting students’ CT, the perspectives of students as well as of teachers are examined. To evaluate the effectiveness of the course from the students’ perspective, the video and audio data, the students’ works, students’ interviews or questionnaires are inductively analyzed using the constant comparative method to identify the students’ learning processes. The results show that students apply content knowledge, apply CT skills, and demonstrate a disposition toward CT. This corresponds to a developed CT. Further analysis is conducted to relate the design skeleton facets of the course (materials, activity structure, and participant structure) to the learning processes, using the conjecture map framework to support the results from the constant comparative method. A Particle Physics Critical Thinking (PPCT) test is also developed to triangulate the results. The results of administering the PPCT test as a posttest are consistent with the qualitative findings on the effectiveness of the course. A questionnaire is developed for teachers to elicit their perceptions of the relevance, practicality, and effectiveness of the course in promoting students’ CT. The results show a positive perception. Combining all the results shows that the antimatter course is an effective course in promoting CT. The design principles applied contribute to the theory of designing effective CT instruction. Furthermore, data analysis reveals the challenges students face in critical thinking and provides teachers with heuristics for designing a domain-specific course. Based on the findings, a model for teaching CT is developed. This work leads to implications for teaching, in addition to other research questions. These include, for example, developing domain-specific CT instruction using 6 principles empirically tested in this study, considering heuristics for designing domain-specific CT instruction, and using the course materials for the purpose of developing CT. In addition, the PPCT can guide the development of other domain-specific CT tests.