A digital microfluidic (DMF) system based on electrowetting on dielectrics (EWOD) is a new technology that is able to manipulate microlitre droplets on the plane. Conventional EWOD devices have difficulty achieving high integration and a large number of electrodes due to the limitation of electrical connections. To realize the precise control of multiple droplets in a large-area EWOD device, we propose a programmable high integration and resolution DMF device based on a thin film transistor array (TFTA) -EWOD in this paper. The TFTA backplane with thousands of individually addressable electrodes used in electrowetting displays (EWDs) is integrated into this device. A source integrated circuit (IC) and a gate IC are bonded on the substrate glass of the device as the driver chip. A TFTA-EWOD device with 320 × 240 electrodes is designed, fabricated and tested in our experiments. Furthermore, a matching droplet control system with detection and feedback functions was developed and implemented. This system is capable of detecting and analysing individual droplet status while concurrently continuing with other droplet manipulations on the TFTA-EWOD device. The experimental results show that different droplet manipulations, including dispensing, merging and transport, can be carried out successfully on this device. We also successfully applied the proposed device and system to a colorimetric enzymatic assay to show that the proposed scheme is capable of chemical analysis experiments. There are no additional errors introduced by the proposed TFTA-EWOD device. The designed device and matching system proposes a programmable high integration, high resolution, and universal solution for complex DMF applications. We hope that the proposed device and system can provide an experimental platform to other research teams who focus on DMF applications.INDEX TERMS Electrowetting on dielectric, digital microfluidic, thin film transistor array, integration.