The paper studies the microstructure stability of a Y2O3-bearing Ti–48Al–2Cr–2Nb alloy during creep. Tensile creep tests were performed at 800–850 °C under 100 or 275 MPa. Compared to thermal exposure, the low creep stress promotes the microstructure degeneration of lamellar colonies, mainly including α2-lath dissolution, γ-lath coarsening and βo phase precipitation. The high creep stress further accelerates the α2 → γ transformation, but goes against the precipitation of βo grains inside α2 laths. Similarly, more Cr-rich precipitates with the composition of Ti(Al, Cr)2 are observed in creep samples, which are identified as the C14-Laves phase. It has a {0001}C14//{111}γ and <101¯0>C14//<11¯0>γ orientation relationship with the γ phase. The high imposed stress also facilitates the precipitation behavior. It should be noted that there are a few C14-Laves phases precipitating along the Y2O3 interface by heterogeneous nucleation. The high strain energy around Y2O3 particles, especially under the high creep stress, contributes to the precipitation of C14-Laves phase not only at the Y2O3 interface, but also in the γ matrix.