Embedding clinically relevant learning experience in basic science subjects is desired for the preclinical phase of undergraduate medical education. The present study aimed to modify case-based learning (CBL) with a role-playing situational teaching method and assess the student feedback and learning effect. One hundred seventy-six sophomore students majoring in clinical medicine from Harbin Medical University were randomly divided into two groups: the control group (n = 90), who received traditional hybrid teaching, and the experimental group (n = 86), who received the role-playing situational teaching. Students in the experimental group were given a 1-wk preclass preparation to dramatize a hyperthyroidism scenario through online autonomous learning of thyroid physiology and performed the patient's consultation process in class, followed by a student presentation about key points of lecture content and a question-driven discussion. A posttest and questionnaire survey were conducted after class. The test scores of the two groups had no statistical differences, whereas the rate of excellence (high scores) of the experimental group was significantly higher than that of the control group. Furthermore, the record of online self-directed learning engagements was significantly improved in the experimental group. In the questionnaire, >70% of the students showed positive attitudes toward the role-playing situational teaching method and were willing to participate in other chapters of the physiology course. Such results show that CBL supported by a role-playing situational teaching method encourages active learning and improves the application of basic knowledge of physiology, which can be incorporated in the preclinical curricula to bridge the gap between theory and practice.