The effects of a 10.5 M solution of aqueous urea on Helicobacter pylori urease were investigated over the course of a 500 ns molecular dynamics (MD) simulation. The enzyme was solvated by 25321 water molecules, and additionally, 4788 urea molecules were added to the solution. Although concentrated urea solutions are known laboratory denaturants, the protein secondary structure is retained throughout the simulation largely because of the short simulation time (urea denaturation occurs on the millisecond time scale). The relatively constant solvent accessible surface area over the last 400 ns of the simulation further confirms the overall lack of denaturation. The wide-open flap state observed previously in Klebsiella areogenes urease [Roberts, B. P., et al. (2012) J. Am. Chem. Soc. 134, 9934] and H. pylori [Minkara, M. S., et al. (2014) J. Chem. Theory Comput. 10, 1852-1862] was also identified in this aqueous urea simulation. Over the course of the trajectory, we were able to observe urea molecules entering the active site in proportions related to the extent of opening of the active site-covering flap. Furthermore, urea molecules were observed to approach the pentacoordinate Ni2+ ion in position to bind in a manner consistent with the proposed initial coordination step of the hydrolysis mechanism. We also observed a specific and unique pattern in the regions of the protein with a high root-mean-square fluctuation (rmsf). The high-rmsf regions in the β-chain form a horseshoelike arrangement surrounding the active site-covering flap on the surface of the protein. We hypothesize that the function of these regions is to both attract and shuttle urea toward the loop of the active site-covering flap before entry into the cavity. Indeed, urea is observed to interact with these regions for extended periods of simulation time before active site ingress.