Hydrodynamic cavitation (HC) has been extensively studied for the Advanced Oxidation of organic compounds in wastewaters since it physically produces an oxidative environment at ambient conditions. This process is simple and economical since it can be realized through a properly designed restriction in a pipeline, even in retrofit solutions. Several experimental works individuated similar values of the optimal operating conditions, especially with regard to the inlet pressure. Up to now, the available modeling works rely on a single-bubble dynamics (SBD) approach and do not consider the actual process configuration and pollutant transport in proximity to the oxidizing environment. This work describes different experimental results (from this research group and others) and applies a novel mathematical model based on a transport-phenomena approach, able to directly simulate the effect of HC on the pollutant degradation. The novel proposed model is able to reproduce well a large number of experimental data obtained in different conditions, with different apparatus and different molecules, and allows to interconnect both SBD, fluid-dynamics, and physio-chemical variables in order to deeply study the interaction between the transport of pollutants and the reactive environment. This paper includes collection and discussion of several experimental results with the related main process parameters, description of the novel model and validation against the cited experimental results (to explain the effect of the operating pressure), sensitivity analysis, and the performance limit of the HC with the proposed modeling approach.