Exocrine pancreatic insufficiency (EPI) causes fat malabsorption, which can increase intestinal oxalate uptake and promote calcium oxalate kidney stone formation. The aim of this study was to develop a porcine model of EPI-associated hyperoxaluria and nephrolithiasis, and to evaluate whether pancreatic enzyme replacement therapy (PERT; Creon^®) reduces renal injury. A randomised controlled experiment included eight pigs: six underwent pancreatic duct ligation to induce EPI and were allocated to the EPI group (n = 3) or the EPI+Creon group (n = 3), while two healthy pigs served as comparators. All pigs were fed a high-fat diet; EPI groups additionally received potassium oxalate monohydrate supplementation (2%, followed by 3%). The EPI+Creon group was administered porcine pancreatic enzymes. Blood and urine samples were collected at predefined time points for measurement of oxalate and creatinine levels. At study termination, kidneys were assessed for calcium oxalate deposition using Pizzolato staining and for histopathological damage using semi-quantitative scoring. Oxalate supplementation significantly increased urinary and plasma oxalate concentrations in pigs with EPI (P < 0.05) and was associated with higher plasma creatinine at the 3% oxalate dose (P = 0.005). Calcium oxalate deposits were markedly more abundant in the renal cortex, medulla, and pelvis in EPI pigs than in EPI+Creon and healthy animals (P < 0.001). Severe glomerular sclerosis, tubular atrophy, and interstitial fibrosis were observed in EPI pigs and were only partially attenuated by PERT. In conclusion, oxalate-fed pigs with EPI develop hyperoxaluria, nephrolithiasis, and renal injury. PERT reduces but does not fully prevent these biochemical and structural kidney abnormalities.