Tidal liquid ventilation (TLV) was proposed as an alternative to conventional mechanical ventilation in the case of surfactant-deficiency diseases, particularly for very premature subjects. Although many experimental studies have been conducted up to now, the effects of variations in ventilatory settings, such as frequency and tidal volume, on blood arterialization and lung mechanics have not been studied quantitatively. We developed a mathematical model simulating the breathing processes occurring during neonatal TLV treatments. The model integrates the description of O2 and CO2 transport, from the trachea to pulmonary capillary blood and vice versa, with the description of fluid mechanics within the airways and the saccules (the alveoli precursors). Gas transfer is described with a mono-dimensional model, accounting for convective and diffusive transport through the airways, coupled with a 3-compartment model, simulating gas diffusion between saccules, plasma and red blood cells, and chemical reactions dependent on the concentrations of gases and related chemical species. Mechanic loads on airways are calculated by means of a lumped-parameters approach. The model calculates mechanical stress and gas exchange as a function of the ventilatory settings. The integration of these results sheds light on possible ventilation strategies to allow for optimal management of blood arterialization and lung mechanical load.