TiAl-based alloys are promising light weight structural materials for high temperature applications in the field of aerospace. Recently, fabrication technologies starting from powders including powder metallurgy and additive manufacturing have been developed to overcome the difficulties in the processing, machining and shaping of TiAl-based alloys. Spherical alloy powders with different particle size distributions are usually used in these fabrication techniques. The purpose of this study is to reveal the size-dependent structural properties of a high-Nb TiAl powder for these fabrication technologies starting from powders. A high-Nb TiAl pre-alloyed powder with nominal composition of Ti-48Al-2Cr-8Nb (at. %) was prepared by the electrode induction melting gas atomization (EIGA) method. The phase structure and morphology of the as-atomized powders were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The size-dependent structural changes of the as-atomized powders with different sizes were studied by differential scanning calorimetry (DSC) and in situ high temperature XRD. It was found that with decreasing the powder size, the content of the γ-TiAl phase decreases and the α2-Ti3Al phase increases. The α2-Ti3Al to γ-TiAl phase transformation was found in the temperature range of 600–770 °C. Based on the present work, the structural characteristics of TiAl powders are strongly dependent on their particle size, which should be considered in optimizing the process parameters of TiAl alloys fabricated from powders.