【Objective】 To explore the effects and mechanism of p38 mitogen activated protein kinase (MAPK) pathway on the formation of calcium oxalate (CaOx) kidney stones in rats,so as to provide new ideas for the treatment of kidney stones. 【Methods】 A total of 40 rats were divided into control, SB203580, CaOx and SB203580+CaOx groups, with 10 rats in each group.Intragastric administration of a mixture of 1% ethylene glycol and 1% ammonium chloride was given to the CaOx and SB203580+CaOx groups to construct CaOx models, while intragastric administration of drinking water was given to the control and SB203580 groups.After molding, SB203580 and SB203580+CaOx groups were injected with 5 mg/kg SB203580 peritoneally once a day for 14 days, while the control and CaOx groups were injected with equal volume of normal saline.The renal mass of rats was measured and the renal coefficient was calculated; the serum levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were measured with an automated biochemical analyzer; the urinary levels of neutrophil gelatinase-associated lipid carrier protein (NGAL) and kidney injury molecule-1 (KIM-1) were determined with enzyme-linked immunosorbent assay (ELISA); the crystal deposition and tissue damage in renal tissues were observed with Von Kossa staining; the apoptosis of renal tubule cells was observed with TUNEL; the expressions of autophagy markers in kidney tissues were detected with immunohistochemical staining; the molecular expressions of autophagy-endoplasmic reticulum stress related pathways in renal tissues were determined with RT-qPCR and Western blot. 【Results】 Compared with the CaOx group, the SB203580+CaOx group had increased body mass after molding (P<0.05); decreased kidney mass, kidney coefficient, BUN, SCr, NGAL and KIM-1 levels (P<0.05); alleviated pathological damage of kidney tissues; significantly reduced black crystal; down-regulated proportion of positive TUNEL cells, positive expression area of LC3B and Beclin-1, mRNA expressions of LC3B, Beclin-1, CHOP and GRP78, protein ratio of LC3-Ⅱ/LC3-Ⅰ, and protein expressions of Beclin-1, CHOP and GRP78 (P<0.05); but up-regulated mRNA and protein expressions of p62 (P<0.05). 【Conclusion】 The p38 MAPK pathway is involved in the formation of CaOx kidney stones in rats.Inhibition of this pathway can reduce the formation of kidney stones, which may be related to the regulation of autophagy and endoplasmic reticulum stress.