Adapting anti-predatory defensive strategies to the properties of the environment is critical for survival. Here, I investigated the dependence of mouse instinctive defensive behaviours on memory of the spatial environment, and the neural mechanisms responsible for accurate escape towards refuge. First, using behavioural assays, I show that the choice and execution of defensive behaviours rely on rapidly acquired memory and are promptly updated following acute changes in the environment. In the presence of a known refuge mice escape directly to it, even if this requires approaching the source of threat. Escape is initiated by a memory- guided, accurate head-rotation movement towards the location of the refuge, indicating knowledge of the spatial goal prior to flight start. Second, I demonstrate that the superior colliculus (SC) is essential to accurately orient to shelter during escape, in agreement with its known role in both sensory- and memory- guided head orientation. To identify which upstream areas provide information about refuge location to the SC, I retrogradely traced the SC afferents and performed loss-of- function experiments in candidate areas, which showed that the retrosplenial cortex (RSC) plays a critical role in escape accuracy. Furthermore, channelrhodopsin-2-assisted connectivity studies showed a functional connection between RSC and SC, and chemogenetic inactivation of this projection impaired accurate orientation to refuge during escape. To understand how the RSC and SC control orientation to shelter during escape, I performed simultaneous single-unit recordings from the RSC and SC with Neuropixels probes. Both RSC and SC were found to encode the angular offset between the mouse’s heading and the shelter, at the single-neuron and population levels. Chemogenetic inactivation of SC-projecting RSC neurons disrupts encoding of head-shelter offset in both regions, but it does not compromise the SC motor function during a sensory- orientation task. In summary, I show that escape is a flexible behaviour and its accuracy critically depends on a monosynaptic projection from the RSC to SC. In addition, I show RSC-dependent egocentric encoding of goal direction at SC, an area critical for orientation during escape, providing a possible mechanism for controlling ethologically relevant goal-directed navigation.