Obesity is associated with increased severity of acute pancreatitis (AP). We recently developed a model of AP induced by administration of interleukin (IL)‐12+IL‐18, two cytokines that are elevated in patients with AP. In this model, severe AP develops in obese leptin‐deficient ob/ob mice compared to lean littermates. In the present report, we evaluated the pancreatic response of diet‐induced obesity (DIO) mice to IL‐12+IL‐18. Body weight loss and adipose tissue necrosis were more severe and prolonged in cytokine‐injected DIO compared to lean mice. Edematous AP developed in lean mice, whereas DIO mice developed necrotizing AP. Obese DIO mice developed more severe hypocalcemia, increased liver damage and a heightened acute‐phase response compared to lean mice, although leukopenia and thrombocytopenia were of comparable severity in lean and DIO mice. Serum levels of IL‐6, IL‐10, and IL‐22 were significantly higher in DIO compared to lean mice, whereas interferon‐γ and tumor necrosis factor‐α did not differ between the two groups. In conclusion, obesity induced by high‐fat diet is associated with increased disease severity and duration in the model of AP induced by administration of IL‐12+IL‐18.