Electrowetting-on-dielectric (EWOD) has attracted as one of the effective on-chip cooling technologies. It enables rapid transport of coolant droplets and heat transfer from target heat sources, while consuming extremely low power for fluid transport. However, a sandwiched configuration in conventional EWOD devices only allows sensible heat transfer, which very limits heat transfer capability of the device. In this paper, we report a novel single-sided EWOD (SEWOD) technology that enables two-phase cooling on a single-sided plate. As a result, heat transfer capability of the SEWOD device can be significantly enhanced. A complete set of droplet manipulation functions necessary for active hot spot cooling has been achieved on SEWOD. Hot spot surface modification to hydrophilic makes a droplet stick on a hot spot and maximize its contact area, greatly improving thermal rejection capability of the device. We have demonstrated two-phase cooling on SEWOD. With successive transportation of four droplets with a volume of 30 μL, the hot spot temperature that was initially heated up to 172°C was able to be stably maintained below 100 °C for 475s. This novel SEWOD-driven cooling technique promises to potentially function as a wickless vapor chamber with enhanced thermal managing capabilities.