To enhance air-coupled piezoelectric micromachined ultrasonic transducers (PMUTs) performance, the substitution of the traditional silicon structural layer with a 40 µm-thick polymer (Parylene-C) coupled with aluminum scandium nitride (AlSc30%N) is proposed as a transformative solution leading to 12.8% increase in the sound pressure level (SPL) and boost the total generated charge by 2.8-fold compared to conventional Si-based PMUTs. The finite element (FE) method coupled with statistical design of experiment (DOE) is utilized to optimize the transducer’s performance. The DOE is conducted in two steps. First, a screening step evaluates the impact of line/radial slit patterns, clamp configuration, and shape of the resonant membrane on device transmission/reception sensitivity. Second, an optimization step uses response surface methodology (RSM), based on three key factors selected from the previous screening. In RSM, a second-order polynomial model is fitted to round-trip sensitivity, and a central composite design is used to explore the design space. DOE screening indicates the optimal configuration improves reception by 30% with a 3.4 dB lower transmission and 8% smaller footprint. The quadratic model (RMSE=0.38, R2= 0.84) indicates that decreasing clamp radial width and increasing the number of radial slits enhance round-trip sensitivity.