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Abstract The practical applications of skin‐interfaced sensors and devices in daily life hinge on the rational design of surface wettability to maintain device integrity and achieve improved sensing performance under complex hydrated conditions. Various bioinspired strategies have been implemented to engineer desired surface wettability for varying hydrated conditions. Although the bodily fluids can negatively affect the device performance, they also provide a rich reservoir of health‐relevant information and sustained energy for next‐generation stretchable self‐powered devices. As a result, the design and manipulation of the surface wettability are critical to effectively control the liquid behavior on the device surface for enhanced performance. The sensors and devices with engineered surface wettability can collect and analyze health biomarkers while being minimally affected by bodily fluids or ambient humid environments. The energy harvesters also benefit from surface wettability design to achieve enhanced performance for powering on‐body electronics. This review first summarizes the commonly used approaches to tune the surface wettability for target applications toward skin‐interfaced sensors and devices. By considering the existing challenges, one also discusses the opportunities as a small fraction of potential future developments, which can lead to a new class of skin‐interfaced devices for use in digital health and personalized medicine.