A new methodology for CFD simulation of airflow in the human bronchopulmonary tree is presented. The new approach provides a means for detailed resolution of the flow features via three-dimensional Navier–Stokes CFD simulation without the need for full resolution of the entire flow geometry, which is well beyond the reach of available computing power now and in the foreseeable future. The method is based on a finite number of flow paths, each of which is fully resolved, to provide a detailed description of the entire complex small-scale flowfield. A stochastic coupling approach is used for the unresolved flow path boundary conditions, yielding a virtual flow geometry that allows accurate statistical resolution of the flow at all scales for any set of flow conditions. Results are presented for multigenerational lung models based on the Weibel morphology and the anatomical data of Hammersley and Olson (1992, “Physical Models of the Smaller Pulmonary Airways,” J. Appl. Physiol., 72(6), pp. 2402–2414). Validation simulations are performed for a portion of the bronchiole region (generations 4–12) using the flow path ensemble method, and compared with simulations that are geometrically fully resolved. Results are obtained for three inspiratory flowrates and compared in terms of pressure drop, flow distribution characteristics, and flow structure. Results show excellent agreement with the fully resolved geometry, while reducing the mesh size and computational cost by up to an order of magnitude.