Although the efficacy of celecoxib on various cancer cell behaviors, including aberrant proliferation, in cultured hepatocellular carcinoma (HCC) cells has been demonstrated, whether celecoxib regulates cell proliferation by targeting PRL-3-associated signaling transduction during hepatocarcinogenesis in vivo has been incompletely studied. Here, we investigate the anti-proliferative efficacy of celecoxib in a rapid HCC mouse model established by hydrodynamic transfection of activated AKT and c-Met proto-oncogenes. The results show that celecoxib is effective at delaying the malignant transformation of hepatocytes by reducing the protein expression of Ki67, Cyclin D1 and c-Myc in the AKT/c-Met HCC-bearing mice. Mechanistically, celecoxib increases the protein expression of PTEN and suppresses the protein expression of NF-κB and PRL-3 in the liver of the HCC mice. Using PTEN-silenced and LPS-stimulated approaches in vitro, a mechanism by which celecoxib regulates a PTEN/NF-κB/PRL-3 pathway in HCC cells was illuminated. Altogether, our study demonstrates that celecoxib attenuates the hepatocellular proliferative capacity during hepatocarcinogenesis, which is probably attributable to its regulation of the PTEN/NF-κB/PRL-3 pathway.