Droplet ejection technology is widely used in green and intelligent manufacturing. A stable jetting can be defined as no obvious satellite droplets during the whole ejection process, which is of great importance to ensure the quality and efficiency of the printed products; However, due to the multi-parameter features and the interaction between different physics, using traditional analytical-based approaches to analyze and/or optimize is usually difficult and even unfeasible. Experimental tests using a PZT printhead design-optimization method based on surrogate modeling are proposed in this paper to overcome this challenge, which can synthesize the advantages of numerical simulation. The basic data for surrogate model construction was obtained by the Computational Fluid Dynamics (CFD) numerical-based model, which was developed to predict the flow characteristic under different parameter settings of the printhead. The accuracy of the developed numerical model was validated by performing experimental tests; thereby, the predictive ability of the numerical model in droplet ejection was verified. With the validated numerical model, the Design of Experiments (DoE) was performed to generate the necessary training and validation sample dataset required by the surrogate modeling. Thereafter, four surrogate modeling methods were adopted to construct the relationship between the design parameters and flow features, where the Kriging (KRG) was identified as the optimal modeling method. Based on the developed KRG model, global sensitivity analysis (GSA) of the parameters was carried out with Sobol’s method; thereby, the influence of different parameters can be quantified. Finally, a genetic algorithm (GA) was used to optimize the structure of the droplet printhead. Through validation, the optimized design model increases the droplet ejection speed by 20.84% while keeping no satellite droplet formation, confirming the efficient and stable printhead ejection, and verifying the feasibility and effectiveness of the analysis/optimization method proposed in this paper.