In this study, generation 5 (G5) polyamidoamine (PAMAM) dendrimers with two different surface groups, G4.5-COOH and G5-OH, were investigated for their protective effects on pancreas injury in a caerulein-induced acute pancreatitis (AP) mouse model. Both dendrimers significantly decreased pathological changes in the pancreas and reduced the inflammatory infiltration of macrophages in pancreatic tissues. In addition, the expression of pro-inflammatory cytokines was significantly inhibited by the two dendrimers, not only in pancreatic tissues from AP mice but also in vitro in mouse peritoneal macrophages with LPS-induced inflammation. G4.5-COOH, which had better in vivo protective effects for AP than G5-OH, led to a significant reduction in the total number of plasma white blood cells (WBCs) and monocytes in AP mice, and its anti-inflammatory mechanism was related to inhibition of the nuclear translocation of NF-κB in macrophages.