Using in situ field effect transistor (FET) characterization combined with the molecular beam epitaxy technique, we demonstrate a significant depletion of electron charge carriers in single zinc oxide (ZnO) nanowire through the surface modification with molybdenum trioxide (MoO3) and 1, 4, 5, 8, 9, 11-hexaazatriphenylene hexacarbonitrile (HATCN) layers. The electron mobility of ZnO nanowire was found to sharply decrease after the surface modification with MoO3; in contrast, the electron mobility significantly increased after functionalization with HATCN layers. Such depletion of n-type conduction originates from the interfacial charge transfer, corroborated by in situ photoelectron spectroscopy studies. The air exposure effect on MoO(3-) and HATCN-coated ZnO nanowire devices was also investigated.