The current study begins with an experimental investigation focused on measuring the pressure drop of a water–air mixture under different flow conditions in a setup consisting of horizontal smooth tubes. Machine learning (ML)-based pipelines are then implemented to provide estimations of the pressure drop values employing obtained dimensionless features. Subsequently, a feature selection methodology is employed to identify the key features, facilitating the interpretation of the underlying physical phenomena and enhancing model accuracy. In the next step, utilizing a genetic algorithm-based optimization approach, the preeminent machine learning algorithm, along with its associated optimal tuning parameters, is determined. Ultimately, the results of the optimal pipeline provide a Mean Absolute Percentage Error (MAPE) of 5.99% on the validation set and 7.03% on the test. As the employed dataset and the obtained optimal models will be opened to public access, the present approach provides superior reproducibility and user-friendliness in contrast to existing physical models reported in the literature, while achieving significantly higher accuracy.