Background: Cyclooxygenase-2 (COX-2) is an enzyme responsible for inflammatory responses and is associated with pain, fever, pyretic diseases, and tumor development. The present study aimed to identify new compounds that could be developed as selective inhibitors for COX-2 isoenzyme by using in-silico approaches. This study was conducted to search for potential anti-inflammatory compounds. Methods: The physiochemical and drug-like properties of natural compounds were determined by SWISSADME and toxicity by using ProTox-II. In-silico docking was performed to determine the affinity of various compounds with a target protein. Molecular dynamic analysis of the protein was carried out using Normal mode analysis (NMA) with internal coordinates normal mode analysis server (iMODS). Non-protein contacts were visualized using Protein Contacts Atlas. Protein-protein interactions (PPIs) were estimated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). The free binding energies of the docked protein-ligand complexes were determined using Fast Amber Rescoring (farPPI). Prospective binding pockets in the protein were identified using DoGSiteScorer. Amino acid variation between the query and the database sequence were determined using BlastP analysis. Results: All the compounds in the present study followed Lipinskis rule of five. ProTox-II analysis revealed that syringic acid, eugenol, and gingerenone A were inactive for all toxicities, whereas isosilychristin was active for immunotoxicity. Isosilychristin was found to be the most effective compound with the highest binding affinity of –10.1 kcal/mol. Molecular dynamic analysis provided insights about the mobility, flexibility and stability of the protein molecule. Protein Contact Atlas analyzed the network of residue-residue interactions at the atomic level. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) provides insights about protein-protein interactions (PPIs), extent of their similarities and functional associations. ShinyGO findings revealed that ovarian steroidogenesis was the predominant pathway. Homology modelling revealed that 96.90% of the residues were found to lie in the Ramachandran favored region. Protein Structure Analysis (ProSA) determined the overall quality of a protein molecule, with a Z-score of –8.91. Molecular Mechanics/Generalized Born Surface area (MM/GBSA) approach described stronger binding affinities between the protein and the ligand molecules. The findings obtained from DoGSiteScorer revealed binding pockets properties with COX-2/isosilychristin complex having the highest surface-volume ratio. BlastP findings revealed that our query sequence showed 100% similarity with prostaglandin G/H synthase 2 (accession number NP_000954.1) and with Crystal Structure of Aspirin Acetylated Human Cyclooxygenase-2 (5IKQ_A and 5F1A_A). Conclusions: The findings of this study revealed that isosilychristin could be a promising inhibitor to target COX-2.