Methods and systems for optimizing perivascular neuromodulation therapy using computational fluid dynamics. Digital data regarding three-dimensional imaging of a target blood vessel and corresponding hemodynamic data are inputs to generating a computational fluid dynamics (CFD) model. The CFD model enables identification of one or more regions of the vessel suitable for neuromodulation therapy and/or identifying one or more regions of the vessel to avoid during such therapy. A system of the present technology can include a neuromodulation catheter, a computing device that can generate and analyze the CFD model, and a user interface for displaying the vessel with indicia for target regions and/or avoidance regions.