Resistive humidity sensors are required in flexible and integrated devices. Two-dimensional MoO3 offers a large interface area, enabling the modulation of its electrical properties over a wide range. In this study, 2D MoO3 was synthesized via liquid-phase exfoliation for humidity-sensing tests. In terms of high sensitivity, negligible hysteresis, linearity, and stability, the humidity-sensing performance of MoO3 is superior to those of other materials. The sensitivity reaches 9794 Ω/RH at 25 °C. The sensing mechanism of MoO3 was investigated by using impedance spectra and voltage-current scans under different humidity levels. The results indicate that the resistance change of MoO3 due to humidity originates from the interfacial conductance. Interfacial H2O adsorption induces efficient conducting paths via hydrogen bonding, decreases the potential barrier for electron transfer, and supplies additional electron states to the valence bands. In this study, electronic humidity sensing was investigated in depth, and a new perspective was proposed for electronic humidity sensing.