A novel Hydrodynamic Cavitation-Assisted Oxygen Plasma (HCAOP) process, which employs a venturi tube and oxygen injection, has been developed for enhancing the production and utilization of hydroxyl radicals (·OH) in the degradation of organic pollutants. This study has systematically investigated the fluid characteristics and discharge properties of the gas-liquid two-phase body in the venturi tube. The hydraulic cavitation two-phase body discharge is initiated by the bridging of the cavitation cloud between the electrodes. The discharge mode transitions from diffuse to spark to corona as the oxygen flow rate increases. The spark discharge has the highest current and discharge energy. Excessive oxygen results in the change of the flow from bubbly to annular and a subsequent decrease in discharge energy. The effects of cavitation intensity, oxygen flow rate, and power polarity on discharge characteristics and ·OH production were evaluated using terephthalic acid as a fluorescent probe. It was found that injecting 3 standard liter per minute (SLPM) of oxygen increased the ·OH yield by 6 times with only 1.2 times increase in power, whereas<0.5 SLPM of oxygen did not improve the ·OH yield due to lower breakdown voltage. Negative polarity voltage increased the breakdown voltage and ·OH yield due to asymmetric density and pressure distribution in the throat tube. This polarity effect was explained by numerical simulation. Using indigo carmine (E132) as a model pollutant, the HCAOP process degraded 20 mg/L of dye in 5 L water within 2 min following a first-order reaction. The lowest electric energy per order (E) was 0.26 (kWh/m/order). The HCAOP process is a highly efficient flow-type advanced oxidation process with potential industrial applications.