Background  Cannabinoids (CBs) evoke their effects by activating the cannabinoid receptor subtypes CB1‐r and CB2‐r and exert anti‐inflammatory effects altering chemokine and cytokine expression. Various cytokines and chemokines are produced and released by rodent pancreatic acini in acute pancreatitis. Although CB1‐r and CB2‐r expressed in rat exocrine pancreatic acinar cells do not modulate digestive enzyme release, whether they modulate inflammatory mediators remains unclear. We investigated the CB‐r system role on exocrine pancreas in unstimulated conditions and during acute pancreatitis. Methods We evaluated in vitro and in vivo changes induced by WIN55,212 on the inflammatory variables amylasemia, pancreatic edema and morphology, and on acinar release and content of the cytokine interleukin‐6 (IL‐6) and chemokine monocyte chemo‐attractant protein‐1 (MCP‐1) in untreated rats and rats with caerulein (CK)‐induced pancreatitis. Key Results In the in vitro experiments, WIN55,212 (10⁻⁶ mol L⁻¹) inhibited IL‐6 and MCP‐1 release from acinar cells of unstimulated rats and after CK‐induced pancreatitis. In vivo, when rats were pretreated with WIN55,212 (2 mg kg⁻¹, intraperitoneally) before experimentally‐induced pancreatitis, serum amylase, pancreatic edema and IL‐6 and MCP‐1 acinar content diminished and pancreatic morphology improved. Conversely, when rats with experimentally‐induced pancreatitis were post‐treated with WIN55,212, pancreatitis worsened. Conclusions & Inferences These findings provide new evidence showing that the pancreatic CB1‐r/CB2‐r system modulates pro‐inflammatory factor levels in rat exocrine pancreatic acinar cells. The dual, time‐dependent WIN55,212‐induced changes in the development and course of acute pancreatitis support the idea that the role of the endogenous CB receptor system differs according to the local inflammatory status.