The aim of this work is to describe and characterize a new spray-drying procedure for the production of nasal powders as an alternative to the conventional freeze-drying method. Cyanocobalamin was chosen as the active ingredient and loaded into five different nonsoluble vehicles with high water absorption ability. Then these hydrated particles were suspended in methylene chloride and spray-dried. Particle size, morphology, true, bulk and tapped density, percentage of compressibility, moisture content, water intake, and drug diffusion were studied and significant differences were obtained depending on the nature of the vehicle. The drying method, either the new spray- or the conventional freeze-drying, was less important. Interestingly, an inverse correlation was found between water uptake and drug diffusion. Microcrystalline cellulose, dextran microspheres, and crospovidone were chosen for an in vivo bioavailability study in rabbits. Three other nasal reference formulations and an intravenous solution were also administered. The spray-dried powders showed higher bioavailability than the three nasal reference formulations. The highest absorption enhancement was observed with cellulose microcrystalline powders, which provided a 25% mean absolute bioavailability, followed by crospovidone and dextran microspheres formulations with mean bioavailability values of 14% and 7%, respectively. In conclusion, the new spray-drying method is useful for the production of cyanocobalamin nasal powders.