The digital microfluidic system (DMF) based on dielectric wetting (EWOD) effect can realize the movement, splitting, synthesis and other operations of multiple droplets at micro rise level. To reduce the cross contamination between heterogeneous droplets of EWOD devices, the completion time of chemical synthesis and biochemical testing in EWOD devices, and ensure the reliability of devices, this paper makes a spatial modeling of DMF system environment through MATLAB platform. Based on the basic A * algorithm, the inflection point is taken as the influence factor of the estimated function value and integrated into the droplet collision strategy, an improved A * algorithm for the fluid characteristics of EWOD devices is proposed. Through the simulation of chemical synthesis experiment, the algorithm shows good droplet addressing optimization characteristics. Compared with the basic A * algorithm, under the same path length (64 electrodes), this algorithm can effectively reduce the redundant inflection points (reduce 10) and the time for droplets to reach the target electrode (reduce about 23S). In addition, the improved algorithm also shows good adaptability (only needs 24 time stamps) in the experiments of multi-droplets synthesis under complex conditions (there are unknown and known faults). The experimental results show that the proposed droplet addressing algorithm has good applicability and reliability for multi droplet path planning and scheduling optimization in EWOD devices, and can effectively reduce the completion time of droplet applications in EWOD devices.