The (100) surface of alpha-MoO3 (α-MoO3) should possess overwhelmingly more exposed Mo than the (010), and the exposed Mo has been extensively considered as active site for amine adsorption. However, α-MoO3 (100) has drawn little attention concerning amine sensing mechanism. In this research, adsorption of ammonia (NH3), monomethylamine (MMA), dimethylamine (DMA), and trimethylamine (TMA) is systematically investigated by density functional theory (DFT). All of these four molecules have high affinity to α-MoO3 (100) through interaction between the N and the exposed Mo, and the affinity is mainly influenced by number of methyl group and number of N-connected H. Adsorption and dissociation of water and oxygen molecule on stoichiometric or defective α-MoO3 (100) surface are then simulated to fully understand surface chemistry of α-MoO3 (100) in practical condition. At low temperature α-MoO3 (100) must be covered with lots of water molecule; the water can desorb or dissociate into hydroxyl groups at high temperature. Oxygen vacancy (VO) can be generated considering the annealing process during sensor device fabrication; VO must be filled with O2 molecule, which can further interact with adsorbed water nearby to form hydroxyl groups. According to this research, α-MoO3 (100) must be the active surface for amine sensing and its surface chemistry is well understood. In near future, further reaction and interaction will be simulated at α-MoO3 (100), and much more attention should be paid to α-MoO3 (100) not only theoretically but also experimentally.