Planetary analog mission simulations are essential for testing science operations strategies and technologies. They also teach us how to use terrestrial analogs to inform studies of extraterrestrial environments. Unoccupied aircraft systems (UASs) have great potential for planetary surface exploration as demonstrated by the Mars 2020 Ingenuity helicopter and the in-development Dragonfly mission to Saturn’s moon Titan. Although applications of UAS technology for planetary exploration remain largely unexplored, simulated missions in planetary analog terrains can inform operational best practices. As part of the Rover–Aerial Vehicle Exploration Network project, we simulated a 12 sol UAS mission on Mars in the Holuhraun region of Iceland. The UAS had airborne imaging capability, as well as imaging, sampling, and geochemical analysis capabilities while landed. The mission evaluated the use of these instruments and developed operational strategies for using UASs to explore a planetary surface. Oblique airborne images were essential for mission planning and were used to scout large areas to identify both potential landing sites and targets for focused investigations. The airborne and landed data collected by the UAS allowed for detailed observations and interpretations not possible with analog orbital data sets, resulting in an improved scientific return for the simulated UAS mission compared to a premission analysis of only the analog orbital data. As a planetary exploration vehicle, a UAS is most advantageous for exploring large areas (many square kilometers) and is particularly useful when the terrain may be impassable to ground-based traverses (e.g., by rovers or humans).