Aim To investigate the mechanism by which hawthorn-derived exosome-like nanovesicles (HDELN) on inhibiting the activation of rat cardiac fibroblasts (RCF) induced by angiotensinⅡ(AngⅡ) and transforming growth factor-β (TGF-β). Methods Primary RCF was extracted and cultured in vitro. RCF activation was induced by AngⅡ and TGF-β, and the cell viability was detected by CCK-8 assay. Western blot was used to detect protein expression levels. RT-qPCR was used to detect the mRNA expression levels. Cell scratch assay was used to detect cell migration ability. siRNA was transfected into RCF to construct a cell model with low expression of SRY-box transcription factor 9 (SOX9) low expression cell model. Results CCK-8 results showed that AngⅡ and TGF-β could enhance the cell viability of RCF (P＜0.05). RT-qPCR results showed that AngⅡ and TGF-β upregulated the mRNA expression of typeⅠcollagen α1 (COL1A1), type Ⅲ collagen α1 (COL3A1), α-smooth muscle actin (α-SMA), periostin (Postn), Runt-related transcription factor 2 (RUNX2) in RCF (P＜0.05). Western blot results showed that AngⅡ and TGF-β upregulated the protein expression levels of COL1A1, COL3A1, and α-SMA in RCF (P＜0.05). The results of cell scratch assay showed that AngⅡ and TGF-β markedly promoted the migration ability of RCF (P＜0.05). HDELN was extracted by differential centrifugation and sucrose gradient density centrifugation. The activation of RCF induced by AngⅡ and TGF-β was reversed by the addition of HDELN (P＜0.05). Western blot and RT-qPCR results showed that AngⅡ and TGF-β upregulated the expression levels of SOX9 in RCF, while HDELN downregulated its expression (P＜0.05). After constructing a cell model with low expression of SOX9, the experimental results showed that the activation level of RCF with low expression of SOX9 was significantly lower than that of normal RCF (P＜0.05). Conclusion HDELN can inhibit the activation of RCF induced by AngⅡ and TGF-β via suppressing the SOX9 signaling pathway.