Cyclooxygenase‐2 (COX‐2) is an enzyme that plays a critical role in the formation of biological mediators called prostanoids. These prostanoids consist of prostaglandins that are a class of signaling molecules, which are responsible for the inflammation and pain processes that occur as an anticipated immune response in our body. COX‐2 inhibitors are a type of anti‐inflammatory drugs (NSAIDs) that directly select, target and block the COX‐2 enzyme. Blocking this enzyme prevents the production of those chemical stimuli that cause inflammation (pain and swelling), arthritis and fever. A few common examples of COX‐2 inhibitors drugs are acetylsalicylic acid (common name: aspirin), celecoxib (brand name: Celebrex) and rofecoxib (brand name: Vioxx). However, since December 2011, Celebrex is the only COX‐2 inhibitor currently used in the United States because data from clinical trials revealed that other medicines such as Rofecoxib (Vioxx) and valdecoxib (Bextra) increased the risk of heart attacks and strokes with long‐term use. Aspirin as a safe alternative is an anti‐inflammatory drug that inhibits the COX‐2 enzyme. COX‐2 triggers inflammation as an innate physiological response. Thus, in blocking COX‐2, aspirin performs as a potent analgesic, anti‐inflammatory and antipyretic. In addition, aspirin blocks COX‐1 the key enzymes in thromboxane TXA2 (a blood‐clotting protein). This is why aspirin is universal over the counter blood thinner or antiplatelet drug. As an irreversible inhibitor, aspirin inhibits the production of prostaglandins and thromboxanes due to its irreversible inactivation of the (COX) enzyme. This action is a result of the ability of aspirin to act on COX‐2 as an acetylating agent with its acetyl group covalently bonded to a serine residue in the active site of the COX enzyme. The goal of this computational study is to fully characterize the aspirin binding mechanism and binding mode in the COX‐2 protein. PDB code 5F1A crystal structure of COX‐2 bound to salicylic acid was utilized since at present, there is no structure solved of the aspirin‐COX‐2 complex. Results of docking with Swiss Dock program indicate that there are two possible binding sites for aspirin in COX‐2. One predicted binding site overlays with Salicylic acid. The other predicted binding site is approximately 8–10 angstroms away within a helix‐turn‐helix structural domain which may be a novel binding site for aspirin. Details of the predicted binding modes, involving amino acids specifically interacting with COX‐2 are represented. More specifically, amino acids of COX‐2 have been identified forming H‐bonds ≤ 3.75 angstroms to aspirin oxygens. Amino acids with hydrophobic interactions < 5.00 angstroms distance from docked aspirin have also been identified. Preliminary results are discussed, including site‐directed mutagenesis studies to confirm the identity of the binding site.