Optimal management of chronic rhinosinusitis (CRS) endotypes includes post-operative application of topical formulations. There is little evidence regarding the ideal aerosol delivery characteristics and techniques to achieve the most efficient deposition on affected sinus mucosa. Nebulisers provide an alternative to nasal sprays by producing smaller particle sizes at lower velocities. We applied a reverse-particle-tracking simulation using computational fluid dynamics (CFD) to evaluate the ideal aerosol characteristics from a nebuliser to target the post-operative maxillary sinus mucosa. A CT scan of a CRS patient was used to create a pre-operative and virtual post-operative model. Particles of diameter 2 to 30 µm were tracked through the sinonasal cavity at 5, 10 and 15 L min–1 flow rates using CFD. Reverse particle simulations demonstrated that the optimised combination of parameters were 20 µm particles, delivered at 5 m s–1 (or 14 microns, delivered at 15 m s–1) at an inhalation rate of 5 L min–1, released from a nozzle in an elliptical oblique-superior direction into the superior half of the nasal valve significantly improved the maximum deposition efficiency (from 3% up to 55%) in the post-operative maxillary sinus mucosa. The nebulised spray (without optimisation) demonstrated negligible particle deposition within the sinuses of the pre-op model, while it increased marginally in the post-op model for smaller diameter particles at lower inhalation rates. The ideal combination of parameters to achieve targeted medication deposition on specific sinus mucosal surfaces can guide the development of new nasal drug delivery devices that produce the desired deposition regions for clinical applications in post-operative CRS patients.