Inhibition of aldose reductase (AR) activity is promising for mitigating diabetic complications. This study proposed a novel screening approach combining PCN-222 metal-organic framework (MOF)-based immobilization-free affinity selection with high-performance liquid chromatography to identify AR inhibitors (ARIs) from natural product extracts. As a proof-of-concept, the AR inhibitory activity of the flowers of Tussilago farfara L. (FTF) was evaluated, and ARIs in FTF were identified using the proposed approach. To validate the screening results, major constituents of FTF were isolated for functional assays, inhibitory kinetics, and interaction mechanisms. The results demonstrated significant inhibitory activity of FTF extracts against AR (IC