Tin oxide (SnO2) represents a major fraction of research for developing solid-state gas sensors. Nevertheless, a detailed insight into the chemical-to-electrical transduction mechanisms between ammonia (NH3) molecules and this metal oxide is still limited. Here, the adsorption of NH3 on SnO2 was examined by density functional theory (DFT) calculations and confronted to experimental data obtained with individual nanowire devices. It was concluded that under real working conditions nonlattice oxygens (O5c) adsorbed on SnO2 exhibit a more basic character than lattice bridging oxygens (O2c), and consequently, they play a key role in the dehydrogenation of NH3 on SnO2, with N2 and H2O as the main resulting products. The sensing process of ammonia on tin oxide nanowires not only involves physical mechanisms but also has a concomitant chemical nature that requires two molecules of NH3 for the reaction to take place. Our theoretical modeling reveals why ammonia sensing is competitive to the adsorption of water molecules. As a result, interfering effects in monitoring traces of NH3 intrinsically occur in humid conditions.