Development of green extractions of natural compounds is an ongoing challenge for researches. The aim of the study was to evaluate the extraction of bioactive compounds (BACs) from oregano combining an experimental procedure with a theoretical approach using two computational simulation methods, Hansen solubility parameters (HSP) and conductor-like screening model for real solvents (COSMO-RS) software. In this study, the high-voltage electrical discharge-plasma (HVED) was used as one of new promising green extraction techniques. Optimization of processing extraction parameters (argon and nitrogen for generation of plasma, voltage?15 kV, 20 kV, and/or 25 kV), frequency (100 Hz), pulse duration (400 ns), and treatment time (3 and 9 min) was done using software STATGRAPHICS. Oregano extracts were prepared by pharmacopoeia, 1 g per 50 mL of solvents (water or aqueous ethanol (25 and 50% v/v) treated by HVED. Extraction process was controlled by analytical methods (determination of total phenolic compounds (TPC); antioxidant properties by electronic paramagnetic resonance (EPR), 2,2-diphenyl-2-picrylhydrazyl (DPPH) free radical assay; near-infrared (NIR) spectroscopy; and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) characterization of phenolic compounds, and changes during and after extraction process were investigated. Process follows six principles of green extractions. Theoretical results were in line with experimental for solvent selection; ethanol had higher potential of solubility of BACs than water. Results showed that HVED, as a green extraction method, confirmed high potential for extraction of BACs from oregano with increased yield of individual BACs and TPC in obtained extracts and increased antioxidant activity, compared with untreated samples.