The development of high-performance sensors is of great significance for the control of the volatile organic compounds (VOCs) pollution and their potential hazard. In this paper, high crystalline V2O5 nanoparticles were successfully synthesized by a simple hydrothermal method. The structure and morphology of the prepared nanoparticles were characterized by TEM and XRD, and the cataluminescence (CTL) sensing performance was also investigated. Experiments found that the as-prepared V2O5 not only shows sensitive CTL response and good selectivity to 2-butanone, but also exhibits rapid response and recovery speed. The limit of detection was found to be 0.2 mg/m3 (0.07 ppm) at a signal to noise ratio of 3. In addition, the linear range exceeds two orders of magnitude, which points to the promising application of the sensor in monitoring of 2-butanone over a wide concentration range. The mechanism of the sensor exhibiting selectivity to different gas molecules were probed by quantum chemistry calculation. Results showed that the highest partial charge distribution, lowest HOMO-LUMO energy gap and largest dipole moment of 2-butanone among the tested gases result in it having the most sensitive response amongst other VOCs.