The study evaluated the effectiveness of a combination of case-based learning (CBL) and flipped classroom (FC) for training residents in axillary venipuncture and catheterization (AVPC). The randomized controlled trial included 46 residents in the reform group (CBL-FC) and 47 in the control group with traditional teaching. The reform group achieved a significantly higher success rate of the first puncture and a shorter operative time (t = 6.474 and 6.459, p < 0.05). Mini-CEX scores in the domains of operational skills, clinical judgment, self-reflection, and professional attitude were higher in the reform group (all p < 0.05). EPA adherence rates were better in the reform group (χ² = 24.373, p < 0.05). Residents in the reform group showed higher satisfaction with content, simulation practice, interaction, methods, and resources (all p < 0.05). The CBL-FC model effectively improves clinical skills and can replace traditional teaching in critical care.