The study designed and implemented a “SPOC (Small Private Online Course) + Flipped Classroom” teaching model for an infectious diseases course. A total of 361 fifth-year clinical medicine students were included; 61 in the experimental group with SPOC-blended teaching and 300 in the control group with traditional lectures. There were no significant differences in baseline demographics between groups (P > 0.05). After the course, students in the experimental group had higher results in academic performance, including the final theory exam and the objective structured clinical examination (OSCE) (P < 0.001). The teaching satisfaction score in the experimental group was higher in all evaluated dimensions, for example "content practicality" 4.4 ± 0.5 vs. 3.1 ± 0.6 and total score 4.5 ± 0.4 vs. 3.2 ± 0.6 (all P < 0.001). The authors conclude that the "SPOC + flipped classroom" model improved academic achievement and clinical practice skills of students and propose it as a feasible path for reforming infectious disease education.