Celecoxib as a nonsteroidal anti-inflammatory agent has hepatotoxicity, increase both oxidative stress and proinflammatory cytokines. The present study investigated the effect of adrenomedullin and omega-3 polyunsaturated fatty acids in celecoxib - induced acute hepatic injury in experimental rats. Fifty Sprague-Dawley rats were divided into five groups; control, celecoxib treated group, celebrex and adrenomedullin treated group, celebrex and omega – 3 treated group, celebrex, adrenomedullin and omega – 3 treated group. Liver functions tests, hepatic oxidants and antioxidants parameters, plasma nitric oxide levels, serum proinflammatory cytokines, plasma PGE2 and adrenomedullin were measured and also histopathological examination was done. Celebrex significantly impaired liver functions, increase hepatic oxidants, decrease hepatic antioxidants, increase proinflammatory cytokines, decrease PGE2 and increase adrenomedullin ,moreover showing necrosis in histopathology. Adrenomedullin and omega-3 PUFAs improved liver functions, decrease oxidative stress, decrease cytokines and PGE2 but nitric oxide level was significantly increased by adrenomedullin whereas decreased by omega-3 PUFAs. There was insignificant change in serum albumin in all groups. Histopathological examination revealed that most of the hepatocytes appeared with normal colored esinophilic cytoplasm and vesicular basophilic nuclei. It could be concluded that celecoxib had an oxidant stress effect in addition to increase proinflammatory cytokines and consequent acute hepatic insult. The development of hepatic injury was celecoxib – dose dependent. Adrenomedullin and omega-3 polyunsaturated fatty acids could alleviate the acute hepatic injury, oxidative stress, decrease proinflammatory cytokines and by turn recovery of hepatic morphology and functions.