Natural products comprise several medicines. The curcumin (CRC) is a constituent of the spice turmeric and part of the mixture of compounds referred to as curcuminoids. The Piperin (PPR) is the major pungent alkaloid present in the fruits of Piper nigrum L. Both have several biological activities, including anti-inflammatory. The inflammatory process is important for tissue homeostasis, however its imbalance is related to several pathologies. Cyclooxygenase-2 (COX-2) participates in the inflammatory process by converting arachidonic acid into prostaglandins (inflammatory mediators). Understanding the connection pattern, at the molecular level, of CRC and PPR with COX-2 can assist in the development of research on natural anti-inflammatories. Comparing the binding pattern of CRC and PPR with COX-2 through molecular docking was the main objective of this study. The docking simulation by AutoDock Vina demonstrated a binding energy with the COX-2 quite similar: for CRC -8.8 Kcal/mol and for PPR -9.0 Kcal/mol. In addition, the binding site at COX-2 was also similar for CRC and PPR. The number of Hydrogen bonds and hydrophobic interactions established with COX-2 was exactly the same for CRC and PPR (01 Hydrogen bond and 12 hydrophobic interaction), however the COX-2 amino acids involved in these bonds were not the same. The energy patterns, location and types of binding established with COX-2 were similar for CRC and PPR, so the anti-inflammatory properties may be similar. In this sense, it would be important to continue in vitro and in vivo studies with both molecules.