Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastric mucosal damage and gastric ulceration. Among the most commonly used NSAIDs, indomethacin upregulates mucosal tumor necrosis factor-α, which activates nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinases (MAPK) to induce various pro-inflammatory mediators. Polydeoxyribonucleotide (PDRN) is an adenosine A receptor agonist that exerts anti-inflammatory effects. In this study, we evaluated the efficacy of PDRN in the initial treatment of gastropathy against that of ecabet sodium and irsoglandin maleate, which are commonly used medications. The rats were administrated indomethacin once a day for 7 days after 24 h of fasting to induce gastropathy. Rats in the drug-treated groups were orally administrated 500 μL of distilled water containing the drug once daily for 7 days 1 h after indomethacin administration. Indomethacin administration caused mucosal damage and increased pro-inflammatory cytokine release. Both NF-κB and MAPK cascade factors were increased by indomethacin administration. PDRN therapy more potently suppressed the expressions of NF-κB and MAPK cascade factors compared to other drugs. The expression of cyclic adenosine-3',5'-monophosphate was also increased by PDRN treatment in the indomethacin-induced gastropathy rats. These changes led to a reduction in pro-inflammatory cytokines and apoptotic factors, which ultimately promote recovery of damaged gastric tissue. Therefore, PDRN may serve as a new therapeutic option in the initial treatment of NSAIDs-induced gastropathy.