This study was undertaken to confirm the antioxidant effects (electron donating ability (EDA) and ABTS radical scavenging ability) of the water (HSW) and ethanol (HSE) extracts of Hydrangea serrata Seringe on the inhibition of nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and mitogen activating protein kinase (MAPK) phosphorylation, in LPS-induced RAW 264.7 cells. Results of the EDA test reveal that at 500 µg/mL, HSW demonstrates a good DPPH radical scavenging ability greater than 81.71%, whereas HSE demonstrates a scavenging ability greater than 89.56%. Evaluating the scavenging activity of ABTS radicals revealed that at 500 µg/mL, both HSW and HSE show superior scavenging activities of 99.4% and 96.1%, respectively. Determining the anti-inflammatory response showed that exposure to both HSW and HSE reduces the NO production in LPS-induced RAW 264.7 cells in a concentration-dependent manner, as compared to the group treated only with LPS. Moreover, exposure to both HSW and HSE resulted in a concentration-dependent inhibition of iNOS and COX-2 protein expressions. It was further confirmed that phosphorylation in the signaling pathway of MAPK was also significantly inhibited in a concentration-dependent manner. Since inhibition of MAPK phosphorylation inhibits iNOS and COX-2, which subsequently induces the expression of NO, our results indicate that extracts of Hydrangea serrata Seringe inhibit and regulate the production of inflammation-related factors. There are few reports on the antioxidant and anti-inflammatory properties of Hydrangea serrata Seringe extracts. Therefore, considering the data obtained in the current study, we propose that Hydrangea serrata Seringe extracts have the potential to be used as useful anti-inflammatory materials in foods and cosmetics.