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Abrus mollis (MJGC) has been used as a substitute herb for Abrus cantoniensis (JGC) in China. However, an in‐depth comparison on their key metabolites and the mechanism of anti‐inflammation between these two is not available. In this report, high pressure liquid chromatography equipped with mass spectrometry was applied to capture their flavonoid profiles; transcriptomics was adopted to analyze their anti‐inflammatory mechanisms. The results showed that the main flavonoids in MJGC were vicenin‐2, schaftoside and isoschaftoside, while those in JGC were vicenin‐1 isomer and schaftoside isomer. The anti‐inflammatory activity of JGC was slightly stronger than that of MJGC. The number of differential expression genes regulated by JGC was significantly higher than MJGC. JGC regulated 151 (42 up and 109 down) of inflammation related genes, while MJGC regulated 58 (8 up and 50 down) of inflammation related genes. The results of this study provided scientific evidence and guidance for the substitution of MJGC and JGC.