The experimental discovery and theoretical analysis of an epitaxial (2 × 2) honeycomb Nb 2 O 3 monolayer on a Au(111) surface is reported. The oxide monolayer is grown by Nb deposition and subsequent annealing in an oxidizing atmosphere. Scanning tunneling microscopy (STM) images show that the films form a well-ordered honeycomb lattice, and low energy electron diffraction patterns confirm that the films adopt a (2 × 2) periodicity with respect to the Au(111) substrate. Density functional theory (DFT) modeling shows that the Nb atoms are located in Au(111) threefold hollow sites and the O atoms are located in on-top positions. DFT also demonstrates the existence of a strong interfacial interaction characterized by a large electron transfer towards the Au substrate, an increase of the Nb oxidation state, and substantial film rumpling. High-resolution STM images, supported by simulations, are able to discriminate between Nb atoms adsorbed in fcc or hcp hollow sites on the Au(111) substrate.