Multi-well aerosol exposure systems are used in modern toxicology assessment studies to deliver aerosol to a large number of tissue/cell culture samples simultaneously. These systems are designed to control the experimental conditions of a delivered aerosol. In these systems (e.g., those developed by Vitrocell GmbH), the aerosol mixture is delivered perpendicularly to the tissue culture through a trumpet-shaped (flared) pipe. In the well chamber where the tissue/cell culture is exposed, the flow is smooth and laminar, which limits shear forces and potential moisture loss that may damage the tissue/cells. These operating flow conditions also determine the aerosol dynamics and deposition mechanisms within the system. The utility of these systems to evaluate biological responses depends on the quantity of tissue culture. With limited experimental data, evaluating the aerosol deposition via computational means is necessary to predict the deposition efficiency. For our investigations, we employed a recently developed Eulerian Computational Fluid Dynamics solver (available at www.aerosolved.com) for simulations of polydisperse multi-species aerosol transport and deposition. We investigated deposition efficiency using various exposure distances to the tissue culture, aerosol properties, and operating conditions. Terms associated with drag, gravitation, and Brownian diffusion were included in the aerosol equations to predict the deposition of the polydisperse aerosol. Results were verified by comparisons with the available experimental data, and predictions were obtained from the Lagrangian simulations using commercially available software. Within the recommended operating conditions, inertial impaction was found not to affect aerosol deposition, which is driven mainly by the size-dependent sedimentation and diffusion mechanisms. An important implication is that for a wide range of droplet sizes, the delivered dose to the tissue is independent of sampled flow rate. Taking this into account, a simple and robust size-dependent theoretical model of the aerosol deposition efficiency was developed. This theoretical model is based on aerosol characteristics, flow, and geometry inputs without the use of any fitting parameter. It can be applied to various exposure system geometries under different operating conditions, as verified in comparisons with published deposition efficiency data obtained from experiments and computations.