The Flipped Classroom (FC) is a promising method of learning, particularly in medical education. Studies show that FC improves student engagement, achievement, and satisfaction. However, its effectiveness in larger classroom settings remains debated. This study explores the impact of FC on theoretical knowledge and practical skills in cardiopulmonary resuscitation (CPR) among medical undergraduates in larger classes. Findings could inform innovative and effective pedagogical approaches to enhance learning and performance in medical education and training. This quasi-experimental study used a control group and recruited students from the Second School of Clinical Medicine of Southern Medical University in 2019. Students were divided into TL or FC. Each group was further divided into 8 units based on grade point average (GPA) stratification. After 8 months, a CPR skill test was conducted to assess CPR retention. The FC and traditional learning (TL) groups had similar demographics. Time spent studying did not affect academic achievement. However, the FC group had significant improvements in pre-class study completion rates on theory learning platform (82.14% vs 22.73%, P = .000) and skill learning platform (75.89% vs 58.18%, P = .005), pre-class theoretical grade (39.98 ± 7.91 vs 27.89 ± 10.19, P = .00), final theoretical grade (18.04 ± 2.39 vs 16.36 ± 2.22, P = .00), and final skill grade (83.10 ± 8.59 vs 78.24 ± 11.04, P = .00). The FC group also had better CPR skill scores in situational settings after 8 months and increased self-efficacy. The study concludes that FC can improve CPR theory and skill for medical undergraduates in large classes. Additionally, students in FC retain better CPR skills after 8 months, especially for situational CPR.