Objective To study the effect of Liangxue Tuizi Formula (LXTZF) on reactive oxygen species (ROS)-mediated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation in Henoch-Sch?nlein purpura (HSP) rats, and to explore its possible mechanism in the treatment of HSP. Methods Twenty-four rats were divided randomly into four groups: control, model, LXTZF, and compound glycyrrhizin (CG) groups. Except for the control group, a model of HSP was established in the other groups by heat drugs combined with egg albumin. After successful modeling, rats in the LXTZF group were given LXTZF solution 7.47 g/kg, rats in the CG group were given CG solution 13.5 mg/kg by gavage, and rats in the control and model groups were given normal saline solution by gavage once a day for 4 weeks. Samples were collected 8 hours after the last gavage. Skin histopathology changes were observed by hematoxylin and eosin (HE) staining. Serum interleukin (IL)-18 and IL-1β levels were detected by enzyme-linked immunosorbent assay(ELISA). Changes in ROS levels in the skin were detected by immunofluorescence. Apoptosis-associated speckle-like protein (ASC), NLRP3, cysteinyl aspartate specific protease-1 (Caspase-1) mRNA and protein expression levels in rat skin were detected by real-time quantitative polymerase chain reaction (RT-PCR) and immunohistochemistry and Western blot, respectively. Results The skin pathology in the model group showed obvious inflammatory cell infiltration compared with the control group. Serum IL-18 and IL-1β levels were significantly increased (P<0.05), skin ROS levels were significantly increased (P<0.05), and skin ASC, NLRP3, Caspase-1 mRNA and protein expression levels were significantly increased (P<0.05). Inflammatory cell infiltration in the skin tissues of rats was alleviated in the LXTZF and CG groups compared with the model group, while serum levels of IL-18 and IL-1β were significantly decreased (P<0.05). ROS levels in the skin were significantly decreased (P<0.05), and mRNA and protein levels of ASC, NLRP3, and Caspase-1 in the skin were significantly decreased (P<0.05). Conclusions The mechanism of LXTZF in HSP may be related to the inhibition of ROS-mediated NLRP3 inflammasome activation.