In this experiment, the Box–Behnken design (BBD) of the response surface methodology (RSM) was used to optimize the ultrasound-assisted extraction variables (liquid-to-solid ratio, extraction temperature, and time) to obtain the maximum yield of physcion from the methanol extract of S. occidentalis (aerial parts). The analysis of physcion in the extracts obtained by using the optimized extraction condition was carried out in a gradient system by the HPLC-UV method with 0.5% formic acid in ultra-pure water (Solvent A) and acetonitrile (Solvent B) in different ratios as the mobile phase. The optimal extraction conditions for the maximum physcion extraction were found as: a liquid-to-solid ratio of 20.16 mL/g, extraction temperature of 52.2 °C, and extraction time of 46.6 min. Under these optimal ultrasonic extraction conditions, the experimental yield (% w/w of the dried extract) of the physcion was found to be 2.43%, which agreed closely with the predicted value (2.41). The experimental value was consistent with the value predicted by the RSM model, thus validating the fitness of the employed model and the success of the RSM in optimizing the extraction conditions. In future, this optimized ultrasonic extraction condition can be used in the maximum extraction of physcion from marketed herbal supplements containing S. occidentalis as well as other Senna species.