This study aimed to explore the effect of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signalling on Henoch–Schonlein purpura nephritis (HSPN). We established a HSPN rat model in a high-altitude hypoxic (HH) environment. Renal tissue lesions were observed by haematoxylin and Eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL), CD20-postive B cells and CD68-postive macrophage cells were detected by immunohistochemistry, T-cell activation was detected by flow cytometry and toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) signalling was detected by western blot. TAK-242 inhibited the expression of TLR4/NF-κB/NLRP3 signalling related-proteins, decreased the levels of 24?h urinary protein, serum creatinine, circular immune complex (CIC) and kidney immunoglobulin A (IgA), and improved renal histopathological damage in HH-HSPN rats. Furthermore, TAK-242 attenuated the infiltration of CD20 and CD68 into the kidney and increased the percentage of CD3+, CD4+ and CD4+/CD8+ cells in the blood of HH-HSPN rats. The study revealed that suppressing TLR4/NF-κB/NLRP3 signalling improved renal function and histopathological damage, and this improvement was related to inhibiting the inflammatory response and enhancing immune competence.