Hypericum caprifoliatum is a natural source of phloroglucinol derivatives such as hyperbrasilol B, uliginosin B and japonicin A, compounds with pharmaceutical interest due to principally their antidepressant properties. This work studies supercritical fluid extraction to obtain non-volatile compounds from the aerial parts of H. caprifoliatum as well as the influence of the co-solvent as agent of process intensification. The experimental procedures were carried out in a pilot unity. The mathematical simulation of the experimental data was performed by mean of three mathematical models aiming to promote the improvement of the knowledge about this technology. The feasibility of the mathematical model was investigated by mean of fitting of the experimental data obtained. The co-solvents tested were ethanol, water, and water–ethanol mixtures.