Background: Excessive production of reactive oxygen species (ROS) associated with oxidative stress induce tissue injury that might trigger the inflammatory process. Superoxide dismutase (SOD) and cyclooxygenase 2 (COX-2) play a significant role in the inflammation prompt after the overproduction of ROS. Polyphenols compound play an important role in alleviating problem associated with oxidative stress. Hippophae rhamnoides leaves extract contain major bioactive polyphenol compound Ethyl 3,4,5-trihydroxybenzoate (gallic acid ethyl ester [GAE]), Gallic acid (GA) and need to be investigate for its anti-oxidant and anti-inflammatory properties. Objective: The objective of this study is to determine the antioxidant and anti-inflammatory potential of GAE and GA derivatives isolated from H. rhamnoides leaves, in vitro and in silico approach target on COX-2 and SOD receptor. Materials and Methods: The isolated compounds GAE, GA, and derivatives 4-O methyl gallic acid (4-OMGA), pyrogallol (PG) were docked using Schrodinger's (LLC, Cambridge, USA) tools. Further in vitro antioxidant activity was determined using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical anion scavenging activity. The anti-inflammatory activity was evaluated using COX-2 inhibitory assay in lipopolysaccharide-stimulated RAW 264.7 cell line. Results: In silico result showed notable binding affinity of GAE with the SOD and COX-2 receptors followed by GA > PG > 4-OMGA. Experimentally, GAE confirmed promising antioxidant potential (DPPH; half-maximal inhibitory concentration 20.3 ± 2.65), SOD anion at 50 μM as well anti-inflammatory activity by inhibiting the COX-2 activity in RAW 264.7 cell line. Conclusion: The result demonstrated the potential biological activities of GAE, GA, and derivatives. In silico finding may act as precious tools to further unlock these potential therapeutic agents against oxidative stress.