The dynamic spheroidization behavior of Ti2AlNb-based alloy with O lamellae during isothermal hot compression was investigated. The aspect ratio of lamellar O phase decreased at higher compression temperatures and lower strain rates, and more kinked or spherical O phases appeared. The results indicated that deformation conditions have a considerable effect on dynamic spheroidization behavior of Ti–22Al–25Nb alloy, and the correlation between spheroidization fraction and strain follows a Avrami-type sigmoid model. The strains for starting (εc) and finishing (εf) of the dynamic spheroidization determined with the nonlinear fit were 0.10–0.31 and 1.70–5.39, respectively. The εc was higher due to the consumption of compressed strains before the fracture of O lamellae. The kinetic rate of dynamic spheroidization is positively correlated with temperature rise and negatively correlated with strain rate. Dynamic spheroidization was achieved through a combination of shearing and diffusional process during different hot compression conditions.