Acute pancreatitis (AP) is an abrupt inflammation of the pancreatic tissue. The severity of AP varies from mild and self-limiting to severe, potentially fatal, and can affect several organ systems. The most severe type of AP causes multiple organ damage (MOD) due to systemic inflammation. In this study, ambrisentan (AMB), an endothelin A receptor antagonist (ETA), was investigated for its potential to ameliorate L-arginine (L-Arg) induced AP and MOD in rats. AP was induced using L-Arg (100 mg/100 g). Two doses of AMB were tested and compared to N-acetylcystiene (NAC) effect. AMB restored the normal structure of the pancreatic, hepatic, pulmonary, and renal tissues. In addition, it normalized the levels of pancreatic enzymes, lactate dehydrogenase (LDH), serum liver enzymes, and kidney biomarkers. Furthermore, AMB corrected the imbalance in the levels of oxidants/antioxidants caused by L-Arg. In contrast, AMB (5 mg/kg) significantly upregulated the protein levels of adenosine monophosphate protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxidase-1(HO-1) and thioredoxin reductase 1 (TXNRD1) by approximately 69.59 %, 85.14 %, 688 % and 96 % respectively, compared with those in rats treated with L-Arg. Furthermore, AMB (5 mg/kg) significantly lowered the thioredoxin-interacting protein (TXNIP), nod-like Receptor Protein 3 (NLRP3), glycogen synthase kinase-3β (GSK-3β), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), CD68, autophagic markers (P62 and LC3) and apoptotic marker caspase 3 by around 62.43 %, 73.56 %, 62.5 %,70 %, 80.3 %, 93 %, 96.7 %, 95 %, 39.6 % respectively, compared to the group treated with L-Arg. AMB effectively improved the AP and MOD produced by L-Arg through its anti-inflammatory and antioxidant properties. NRF2/HO-1 and TXNIP/NLRP3 pathways play major roles in these protective effects.