The humidity causes incorrect signal transmission of gas sensors in real applications. Humidity-independent acetone gas sensors of Nb-doped CeO2 nanofibers were designed and prepared by electrospinning. The 1% Nb-doped CeO2 sensor exhibits excellent response (23.27), good selectivity, repeatability, and long-term stability. This response is 13.37 times higher than that of the undoped CeO2 sensor (1.74) upon exposure to 100 ppm acetone at 240 °C. The XPS results reveal that the doped Nb element exists as Nb2O5 and can regulate the percentage of Ce3+/Ce4+, thus leading to rich oxygen vacancies and enhanced acetone sensing performance. In addition, the 5% Nb-CeO2 gas sensor exhibits humidity-independent gas sensing. Under humidity conditions, water molecules adsorbed on the active sites of CeO2 will be ionized into H+ as the dominant charged carriers, leading to a large decrease of resistance and enhanced acetone gas sensing; conversely, water molecules chemisorbed on the surface of the doped induced Nb2O5, will induce hydroxyl group, inhibiting acetone gas sensing. Thence, the appropriate Nb dopant can modulate the replacement ratio of H+ to the hydroxyl group, which indicate that proper Nb-doped CeO2 is a promising acetone sensing material in humidity.