Direct measurements of cosmic ray (CR) species combined with observations of their associated gamma-ray emissions can be used to constrain models of CR propagation, trace the structure of the Galaxy, and search for signatures of new physics. The spatial density distribution of interstellar gas is a vital element for all these studies. So far, models have employed the 2D cylindrically symmetric geometry, but their accuracy is well behind that of the available data. In this paper, 3D spatial density models for neutral and molecular hydrogen are constructed based on empirical model fitting to gas line-survey data. The developed density models incorporate spiral arms and account for the warping of the disk, and the increasing gas scale height with radial distance from the Galactic center. They are employed together with the GALPROP CR propagation code to investigate how the new 3D gas models affect calculations of CR propagation and high-energy gamma-ray intensity maps. The calculations reveal non-trivial features that are directly related to the new gas models. The best-fit values for propagation model parameters employing 3D gas models are presented and they differ significantly from those derived with the 2D gas density models that have been widely used. The combination of 3D CR and gas density models provide a more realistic basis for the interpretation of non-thermal emissions from the Galaxy.