Digital microfluidics (DMF) driven by electrowetting-on-dielectric (EWOD) has recently been attracting great attention as an effective liquid-handling platform for on-chip cooling. It enables rapid transportation of coolant liquid sandwiched between two parallel plates and drop-wise thermal rejection from a target heating source without additional mechanical components such as pumps, microchannels, and capillary wicks. However, a typical sandwiched configuration in DMF devices only allows sensible heat transfer, which seriously limits heat rejection capability, particularly for high-heat-flux thermal dissipation. In this paper, we present a single-sided digital microfluidic (SDMF) device that enables not only effective liquid handling on a single-sided surface, but also two-phase heat transfer to enhance thermal rejection performance. Several droplet manipulation functions required for two-phase cooling were demonstrated, including continuous droplet injection, rapid transportation as fast as 7.5 cm/s, and immobilization on the target hot spot where heat flux is locally concentrated. Using the SDMF platform, we experimentally demonstrated high-heat-flux cooling on the hydrophilic-coated hot spot. Coolant droplets were continuously transported to the target hot spot which was mitigated below 40 K of the superheat. The effective heat transfer coefficient was stably maintained even at a high heat flux regime over ~130 W/cm2, which will allow us to develop a reliable thermal management module. Our SDMF technology offers an effective on-chip cooling approach, particularly for high-heat-flux thermal management based on two-phase heat transfer.