Objective To investigate the effects of N-acetyl-D-glucosamine (GlcNAc) on acute pancreatitis in rats. Methods Twenty male SD rats were randomly divided into a control group, AP group, low GlcNAc + AP group and high GlcNAc + AP group, with five rats in each group. Acute pancreatitis was induced in AP group, low GlcNAc + AP group and high GlcNAc + AP group by two intraperitoneal injections of 2.5 g/ kg L-arginine with a 1 hour interval. Among them, low GlcNAc + AP group and high GlcNAc + AP group were administered 50 and 200 mg/ kg GlcNAc, respectively, by intraperitoneal injection at 24 hours before the first intraperitoneal injection of L-arginine. Group control and AP were intraperitoneally injected with the same volume of normal saline. After 24 h, the rats were sacrificed, and serum and pancreatic tissues were collected. Pancreatic tissue morphology was observed by HE staining, and serum levels of amylase (AMY), lipase (LPS), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by enzyme-linked immunosorbent assay. Protein expression of nuclear factor E2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) in pancreatic tissue was detected by Western Blot. Cluster of differentiation (CD)86, CD206 and macrophage markers (F4/80) were detected by immunofluorescence. Expression of CD86 and CD206 in pancreatic tissue was detected by immunohistochemistry. Results (1) Compared with control group, AMY, LPS, IL-1β, IL-6, TNF-α, and MDA levels and pancreatic CD86 expression in AP group were significantly increased (P< 0. 05), while SOD activity, protein expression levels of NRF2, HO-1, and PPAR-γ , and pancreatic CD206 expression were significantly decreased (P<0. 05). (2) Compared with AP group, serum IL-1β, IL-6, TNF-α, MDA, and LPS and the pancreatic CD86 expression in low GlcNAc + AP group were significantly decreased (P< 0. 05). The PPAR-γ protein level in the pancreas was significantly increased (P< 0. 05). (3) Compared with AP group, serum AMY, LPS, IL-1β, IL-6, TNF-α, and MDA and pancreatic CD86 expression in high GlcNAc + AP group were significantly decreased (P< 0. 05), while serum SOD , and NRF2, HO-1, PPAR-γ,and pancreatic CD206 expression were significantly increased (P< 0. 05). (4) Compared with low GlcNAc + AP group, serum LPS, IL-1β and IL-6 in high GlcNAc + AP group were significantly decreased (P<0. 05). Pancreatic expression of HO-1, PPAR-γ, and pancreatic CD206 were significantly increased ( P< 0. 05). Conclusions GlcNAc treatment attenuates acute pancreatitis injury in AP rats, possibly by activating the NRF2/ HO-1 signaling pathway to inhibit oxidative stress and promoting M2 macrophage polarization to attenuate pancreatic injury in AP rats.