Cold plasma is a powerful and eco-friendly technology with potential applications in wastewater treatment, disinfection, and sustainable agriculture. Reactive species produced by the cold plasma discharge can effectively degrade a variety of pollutants. This work focuses on microbubble-enhanced cold plasma activation (MB-CPA) through a self-suction mechanism for water treatment in a flow system. Microbubbles form under the strong turbulence at the throat of a cavitation tube, transferring active species generated from air plasma discharge into the water stream. The degradation rate of a model antibiotic compound, sulfathiazole, is compared by varying the dimensions of the cavitation tube, the flow rate of water, and the distance between the plasma discharge and the flow surface. The width of the air inlet of the cavitation tube is found to be the most important parameter for activation efficiency. Three-dimensional computational fluid dynamics simulations reveal that a higher air volume fraction and more bubbles are created with a wider air inlet. The proxy models generated by using multiple linear regression and an artificial neural network can predict degradation efficiency in good agreement with the experimental data. The optimized portable MB-CPA has the potential for broad applications in wastewater treatment, sustainable agriculture, and environmental remediation.