Abstract In order to better understand the thermal stability and mechanical properties of the nominal Ti–22Al–25Nb alloy with different initial microstructures, microstructural evolution after long-term aging, and mechanical properties at room temperature and 650 °C of four differently heat-treated Ti–22Al–25Nb alloy were investigated. The investigation results indicated that α2 platelets formed by aging at (α2+B2) region were not as stable as previous research claimed and spontaneously decomposed into fine (O+β/B2) mixture during the annealing at 650 °C. As a result, the alloy's steady-state creep strain rate dropped dramatically at the secondary creep stage and tensile strength grew. On the contrary, long time aging exposure resulted in the connection of original dispersed lenticular O precipitation and thus degraded the ductility of all specimens. Besides, the discontinuous precipitation B2→β+O caused by supersaturation of solutes in the matrix also harmed the mechanical properties. Under the condition of 650 °C/250 MPa, the steady-state creep strain rates of the Ti–22Al–25Nb specimens show a significant dependence on their grain size. Crept samples showed that most dislocation motion was restrained in the β channels under a small strain and then extended into O phase when creep strain grew over 10%. Finally, by comparing the room temperature tensile property and creep resistance of four samples, supertransus solution and furnace cooling ensured the alloy most balanced mechanical properties among lamellar samples. The supertransus then furnace-cooled sample did not only have an excellent creep resistance but also kept a moderate room temperature elongation to failure of nearly 6%.