Abstract Objectives The ‘Host Defense and Immunology’ course is compulsory for undergraduate students majoring in clinical medicine at Shanghai Jiao Tong University School of Medicine. In order to promote students’ self-directed and active learning, we innovated teaching activities around ‘seamless learning’ which is emphasising learner-centredness. Methods Guided by the concept of seamless learning, we integrated teaching content, constructed course resources, innovated course-teaching modes, and reformed assessment and evaluation. Then two survey questionnaires were provided to students to get feedback on the course achievement. One set of survey questionnaire with written descriptions was designed to collect feedback on the overall evaluation of the course. Another survey questionnaire was presented in the form of multiple-choice questions to get feedback on more specific questions. Results 294 questionnaires were distributed to eight-year clinical medicine students in years 2021–2022, and 234 were valid. Overall student feedback revealed that the students mastered the immunological basic theories, research techniques and have acquired integrated systematic thinking. The students also deepened their application ability, pursued clinical rigor and logic, and shaped their clinical thinking patterns. The survey questionnaire revealed that the comprehensive immunological mind map was highly beneficial for analysing clinical immunological problems, understanding immunological principles, grasping interrelationships between knowledge points, and fostering self-learning abilities. Case-based learning (CBL), micro-lecture videos, and learning about scientists’ and doctors’ stories also had positive effects on students’ active learning, understanding, logical thinking, innovation, and humanistic literacy, with over 79 % of students reporting benefits. Conclusions Based on seamless learning, students acquired integrated systematic thinking through the course, shaped clinical thinking patterns, developed communication and collaboration skills, and enhanced their ability to analyse and solve clinical problems. The exploration and practice of the ‘Host Defense and Immunology’ course provides a good example for the integration of seamless learning concepts into teaching.