Neuraminidase (NA) plays a biologically vital role in the replication of influenza virus, and NA inhibitors (NAIs) are most widely used in the clinical anti-flu therapy. NA of 2009 H1N1 influenza virus (09N1) possesses a different substrate-binding cavity compared with other NA subtypes, making 09N1 a more appropriate starting point for the discovery of potent 09N1 inhibitors. As natural products are of great structural diversity, research on the interaction between natural NAIs and 09N1 can throw light on the design of new structural NAIs. In this study, we, for the first time, conducted molecular docking procedure with GOLD on 10 natural inhibitors to 09N1, and acquired their binding modes with 09N1. The docking results showed that the active site S1 was important in the binding of NAIs to 09N1. Then five scaffolds were extracted from these NAIs with interactions to site S1, and these could be used in the structural modification of NAIs. Besides, we found that the addition of H-bonding interaction with the active site could improve the NA inhibitory activity of NAIs, and it might be the reason why the approved NAIs showed high efficiency. Two terminal hydrophobic sites (Terminal 1 and Terminal 2) with no interactions to the approved NAI zanamivir were found in the 09N1 active cavity, and four NAIs were first found to bind with the terminals. Till now, there are few studies on the meaning of Terminal 2 in the binding of NAI to NA, which could be a new direction for the rational design of NAIs.