Protein Tyrosine Phosphatase non-receptor type 11 (PTPN11; encoding protein SHP2) is an important protein tyrosine phosphatase (PTP) in the human body and plays an important role in regulating cell proliferation and differentiation. Overexpression of SHP2 will promote the development of cancer diseases, so research on SHP2 inhibitors has become one of the popular targets for the treatment of cancer. Recent studies have shown that combining SHP099 (an allosteric site 1 inhibitor) with SHP844 (an allosteric site 2 inhibitor) will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamics simulations to explore the inhibition mechanism of SHP099 and SHP844 on SHP2 protein. The result shows that the interactions of allosteric site 1 (THR108-TRP112, LEU236-GLN245), allosteric site 2 (GLN79-GLN87, LEU262-GLN269), P-loop (HIS458-ARG465), and Q-loop (ARG501-THR507) are obviously enhanced in SHP2-SHP099-SHP844 system, which makes the fluctuation of residues more stable and the active site more difficult to be exposed. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that led to the SHP2 protein in auto-inhibition conformation. This study provides an idea that help people to understand the mechanism of inhibition of the combining SHP099 with SHP844 on the SHP2.