〔Abstract〕 Objective To investigate the effects and mechanisms of oridonin(ORI) on human keloid-derived fibroblasts(HKF). Methods The effects of ORI on the proliferation activity of HKF were assessed using the CCK-8 assay. The experiment was divided into control and experimental groups. Cell scratch and Transwell assays were conducted to evaluate the migration and invasion capabilities of HKF. Real-time quantitative PCR(RT-qPCR) and Western blot were used to examine the impact of ORI on the expression of extracellular matrix-related mRNA and fibronectin 1(FN1), α-smooth muscle actin(α-SMA), type I collagen( COL I), and COL Ⅲ in HKF. The experiment was also divided into control, model, and transforming growth factor(TGF)-β1+ORI groups. RT-qPCR and Western blot were utilized to determine the effects of ORI on the expression of TGF-β1-induced mRNA and nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), apoptosis-associated speck-like protein containing a CARD(ASC), Smad2, Smad3, phosphorylated Smad2(p-Smad2), and p-Smad3 in HKF. Results CCK-8 assay demonstrated that the cell inhibition rate of HKF progressively increased with increasing concentrations of ORI. Compared with the control group, the experimental group exhibited a significant reduction in the migration area at 24 hours and a decrease in the number of invasive cells. Furthermore, there was a significant downregulation in the expression levels of FN1, α-SMA, COL I, and COL Ⅲ(P<0.05). In comparison with the control group, the model group showed a significant upregulation in the expression of NLRP3, ASC, Smad2, Smad3, p-Smad2, and p-Smad3(P<0.05). Relative to the model group, the TGF-β1+ORI group demonstrated a significant downregulation in the expression of NLRP3, ASC, Smad2, Smad3, p-Smad2, and p-Smad3(P<0.05). Conclusion ORI the proliferation, migration, and invasiveness of HKF, as well as the formation and deposition of the extracellular matrix, through the blockade of the TGF-β1/Smad signaling pathway and the NLRP3-mediated inflammatory response.