Pressure can lead to protein fold and denaturation. As for the element of protein, the study of amino acid under high pressure has attracted attention of scholars in recent years. The properties of some amino acids among 20 common amino acids have been studied by using high-pressure Raman spectroscopy techniquewith the maximum pressure reaching to 30 GPa. In order to investigate the structural change of L-serine (C3H7NO3) under ultra-high pressure, L-serine crystal was studied at room temperature by in-situ high pressure Raman spectroscopy, and it was submitted to pressure up to 22.6 GPa. The results showed that a new peak appears at 102 cm-1 when the pressure reaches 2.7 GPa, and the peak splits at 1 123 cm-1 (NH3 antisym rocking). Furthermore, a new peak appears at 574 cm-1 as the pressure reaches 5.4 GPa, and the original peak at 164 cm-1 disappears. While the pressure reaches 6.0 GPa, new peaks appear at 226, 456, 770, 2 968 cm-1 (CH2 stretching). And one peak splits at 877 cm-1, which produces a new peak at 894 cm-1. When the pressure reaches 7.9 GPa, new peaks appear at 145, 151 and 2 946 cm-1. With the pressure reaching 11.0 GPa, the vibration peak at 249 cm-1 begins to split and a new peak appears at 241 cm-1, which is located at 2 956 cm-1 (CH2 Stretching) while the original peak at 391 cm-1 and 431 cm-1 disappears. When the pressure reaches 17.5 GPa, a new peak emerges at 200 cm-1. By further analyzing the Raman spectroscopy, many Raman peaks have inflexed at pressure of 1.37, 2.2, 5.3, 7.46, 11.0 and 15.5 GPa. These results showed that the crystals undergo seven structural phase transitions, which are in the pressure range of 0.1~1.37, 2.2~2.7, 5.3, 6.0, 7.46~7.9, 10.1~11.0 and 15.5~17.5 GPa, respectively. Moreover, a new phase transition that was found at 6.0 GPa has never been discussed before. This Structural change may be caused by rearrangement of molecules, which is induced by pressure. And molecular rearrangement leads to hydrogen bond rearrangement, which causes new CH2 stretching vibration peak. The Raman spectra in the range of 10.1～11.0 GPa focus on the low wavenumber, which is assigned to the low-energy vibration such as crystal lattice vibration and the new CH2 stretching vibration. So the crystal lattice vibration of L-serine crystal change within 10.1~11.0 GPa, which causes the new hydrogen bond of L-serine crystal to change its structure. No direct evidence of structural phase transition has been found in the 15.5~17.5 GPa pressure range, except for the inflection point at 17.5 GPa. Therefore, it is speculated that L-serine crystals undergo a structural phase transition.