Concurrent with mental processes that require rigorous computation and control, a series of automated decisions and actions govern our daily lives, providing efficient and adaptive responses to environmental demands. Using a cognitive flexibility task, we show that a set of brain regions collectively known as the default mode network play a crucial role in such “autopilot” behavior, i.e. when rapidly selecting appropriate responses under predictable behavioral contexts. While applying learned rules, the default mode network shows both greater activity and connectivity. Furthermore, functional interactions between this network and hippocampal, parahippocampal areas as well as primary visual cortex correlate with the speed of accurate responses. These findings indicate a memory-based “autopilot role” for the default mode network, which may have important implications for our current understanding of healthy and adaptive brain processing.