Prior knowledge structures (or schemas) confer multiple behavioral benefits. First, when we encounter information that fits with prior knowledge structures, this information is generally better learned and remembered. Second, prior knowledge can support prospective planning. In humans, memory enhancements related to prior knowledge have been suggested to be supported, in part, by computations in prefrontal and medial temporal lobe cortex. Moreover, animal studies further implicate a role for the hippocampus in schema-based facilitation and in the emergence of prospective planning signals (...) following new learning. To date, convergence across the schema-enhanced learning and memory literature may be constrained by the predominant use of hippocampally dependent spatial navigation paradigms in rodents, and non-spatial list-based learning paradigms in humans. Here, we targeted this missing link by examining the effects of prior knowledge on human navigational learning in a hippocampally dependent virtual navigation paradigm that closely relates to foundational studies in rodents. Outside the scanner, participants overlearned Old Paired Associates (OPA – item-location associations) in multiple spatial environments, and they subsequently learned New Paired Associates (NPA – new item-location associations) in the environments while undergoing fMRI. We hypothesized that greater OPA knowledge precision would positively affect NPA learning, and that the hippocampus would be instrumental in translating this new learning into prospective planning of navigational paths to NPA locations. Behavioral results revealed that OPA knowledge predicted one-shot learning of NPA locations, and neural results indicated that one-shot learning was predicted by the rapid emergence of performance-predictive prospective planning signals in hippocampus. Prospective memory relationships were not significant in parahippocampal cortex and were marginally dissociable from the primary hippocampal effect. Collectively, these results extend understanding of how schemas impact learning and performance, showing that the precision of prior spatial knowledge is important for future learning in humans, and that the hippocampus is involved in translating this knowledge into new goal-directed behaviors. (shrink)