Ti2AlNb-based composites are a great choice for achieving high-temperature properties by introducing reinforcement to meet engineering application requirements. In this study, Ti–22Al–25Nb (at.%) alloys and nano-Al2O3/Ti–22Al–25Nb composites were prepared by mechanical alloying (MA) and hot pressing (HP). The effects of sintering temperature on the microstructure and mechanical properties of Ti–22Al–25Nb alloys and Ti2AlNb-based composites were investigated. The sintering temperature effectively regulated the morphology and size of the primary O phase. The addition of Al2O3 particles refined the grain size of the matrix and precipitates, and it induced the phase transformation. When the sintering temperature reached 1350 °C, Ti–22Al–25Nb alloys and Ti2AlNb-based composites obtained a fine and uniform equiaxed microstructure. The hardness and ultimate compressive strength of the composite first increased and then decreased with increasing sintering temperature. Since the addition of Al2O3 particles promoted the precipitation of the ultrafine acicular O phase from the B2 phase, the composite sintered at 1350 °C had the optimal mechanical properties. The hardness of the Ti–22Al–25Nb alloy and Ti2AlNb-based composite was 4.12 GPa and 5.1 GPa, respectively. The ultimate compressive strength of the composite at room temperature (RT) and 650 °C was 2642.3 MPa and 2462.5 MPa, which was 25.8% and 9.6% higher than that of the Ti2AlNb alloy. The strengthening mechanism of the composites mainly includes dispersion strengthening and Orowan strengthening of the nano-Al2O3 particles, as well as precipitation strengthening of the acicular O phase. This study provides a theoretical guidance for designing Ti2AlNb-based composites with excellent high-temperature properties.