<p>Industrial wastewater poses significant environmental and health challenges due to its complex composition of organic and inorganic pollutants. This study investigates novel approaches to enhance industrial wastewater treatment efficiency by leveraging hydrodynamic cavitation (HC) processes combined with air injection into the bypass line. Synthetic wastewater, mimicking typical industrial chemical oxygen demand (COD) levels, was treated under various conditions with a fixed capacity of 15 L. The experimental investigation explores the effects of varying inlet pressures and airflow rates on the reduction of COD in wastewater. One reactor was placed in the main line, while another was positioned in the bypass line. Various hybrid approaches based on HC were explored, including HC + Air (injection in the tank), HC + Air (injected into the bypass line), and HC + Air injection (into the throat of the bypass line venturi). The findings reveal that the highest COD reduction, reaching 31.97%, was achieved at an optimized inlet pressure of 5 bar when air was injected at a flow rate of 25 l/min into the throat of the bypass line reactor. Additionally, the percentages of COD reduction for various processes—solo HC, HC+ aeration in the bypass line, and HC in the mainline and bypass line—were observed to be 17.29%, 23.44%, and 24%, respectively. The synergistic effects of combining these strategies are quantified, highlighting substantial improvements in wastewater treatment efficiency. Overall, the current work underscores the potential of innovative HC by injecting air into the bypass line techniques to address the challenges of industrial wastewater treatment and advance environmental sustainability.</p>