Ti2AlNb-based alloys are developed from conventional titanium aluminides (TiAl-based alloys and Ti3Al-based alloys). Comparing with TiAl and Ti3Al-based alloys, Ti2AlNb-based alloys have better mechanical properties of strength density ratio, high temperature fracture toughness and creep resistance. It is expected to replace traditional high temperature materials such as nickel-based alloys for the manufacture of aero-engine components. Laser shock peening (LSP) is an advanced surface modification technology which induces high amplitude, large depth residual compressive stress on the surface of materials. It can effectively enhance mechanical properties of material such as micro-hardness, fatigue resistance, high temperature oxidation performance. Compared to other surface modification technologies such as shot peening and rolling, LSP can not only induce deeper compress residual stress (1–2 mm), which is about five to ten times deeper than that of shot peening, but it can refine the grain or even form nanocrystals which plays a significant role in enhancing properties of material. For these reasons, this surface treatment technology has been widely used in the aircraft and nuclear energy industries. In this paper, the surface modification of Ti2AlNb alloy was carried out by laser shock peening, and the microstructure evolution, residual stress and the performance at high temperature were investigated. The results show that laser shock peening can significantly reduce the grain size of the surface of Ti2AlNb alloy. Dislocation lines, dislocation tangles and dislocation walls were generated after LSP. The micro-hardness is increased from 350 HV to 395 HV and the effect layer is about 1.2 mm. The residual compressive stress of −337 MPa is generated on the surface of the sample. In addition, residual stress is released obviously at high temperature. The residual stress on the surface of sample reduces to −65 MPa after heat treatment at 720°C for 4 h. The residual stress is almost completely released after heat treatment at 720°C for 10 h. However, the release rate of residual stress is slowed down at 600°C. The effect of laser shock peening is still presence after heat treatment for 100 h.