As the recent demand for human resources in science, technology, engineering, and mathematics (STEM), the development of professional STEM teacher is called worldwide. It is becoming a critical need in teacher education in order to educate student teachers, and prepare pre-service and beginning teachers for high quality of teaching competency. To promote the competency for 21st century STEM teachers, the epistemology of technological pedagogical content knowledge (TPACK) is currently considered as the essential qualities of knowledge for highly qualified teachers. The aim of this study is explore the effect of case-based learning approach on TPACK competency of pre-service STEM teachers. In order to develop the pre-service teachers`` competency regarding effective integration of technologies into teaching specific content areas, a series of innovative case study teaching in science and mathematics was presented to 43 participants of pre-service physics, chemistry, biology, mathematics, and computer teachers during a course of information and communication technology (ICT) in Education at Khon Kaen University, Thailand. After finishing a case presentation, the pre-service teachers were encouraged into a forum of critical open discussion by considering the potential impact of the case and the TPACK framework. They were investigated instructional design competency of using ICT tools into student learning process and their personal beliefs about ICT in educational process both before and after. The participant`s reactions and learning was evaluated by using a selfreported questionnaire and an implementation log of content-specific learning process design, respectively. Results showed a change of their beliefs and the transformation of their TPACK competency in STEM teaching. In an effort to better serve the needs of high quality STEM teachers, the results of this study illustrated that the competency of TPACK could be particularly considered as a core attributes for future STEM teachers. By the way, case-based learning approach can play an effective part in preparing and professing the TPACK competency for STEM teachers.