Introduction: Medical students should be trained about the fundamental skills of evidence-based medicine (EBM) during undergraduate medical education curriculum. This article introduces an innovative model for initiation and development of a flipped classroom for teaching EBM to sixth-year undergraduate medical students in Shiraz Medical School, affiliated to Shiraz University of Medical Sciences. Methods: After conducting needs assessment and setting objectives for the program, blended leaning format and flipped classroom strategy were used. A student satisfaction measurement form was designed to evaluate the flipped classroom based on a 5-point Likert scale. The validity of the questionnaire was determined by experts, and the reliability of the questionnaire was 0.86 after a pilot study. We also used the questionnaires based on Berlin questionnaire to measure students' knowledge, attitude, and practice about the EBM course in a pre-and posttest design. The validity and reliability of the questionnaire had been approved in our previous study. Also, the result of a summative examination after finishing the course was used as a measure of course goal achievement. Results: A total of 280 medical students on their sixth year of study participated in the flipped classroom in 6 different rotations. A total of 266 (95%) students passed the course and only 14 (%5) failed. The results of posttest scores based on the EBM domains revealed that the best result was obtained in teaching clinical questions' format (patient, intervention, comparison, and outcome). The lowest posttest scores were in the domain of biostatistics. The overall quality of flipped classroom was reported well by the students. The students stated that the ability to apply knowledge and skills in managing patients were developed in this course. Discussions: In our experience, flipping classroom was a practical and essential activity to educate a large number of medical students about EBM. We acknowledge that the development of deep learning is instructors' responsibility and that implementing blended learning and flipping classroom can facilitate students' knowledge and skills about this important topic. We hope that other medical schools all over the world use the flipped classroom discussed in this article to redesign their classrooms in such a way that enables students to develop necessary skills and get involved in deep learning. This will improve the health of the society in the near future.