Abstract Exploring a novel environment can facilitate subsequent hippocampal long-term potentiation in animals. We report a related behavioral enhancement in humans. In two separate experiments, recollection and free recall, both measures of hippocampus-dependent memory formation, were enhanced for words studied after a 5-min exposure to unrelated novel as opposed to familiar images depicting indoor and outdoor scenes. With functional magnetic resonance imaging, the enhancement was predicted by specific activity patterns observed during novelty exposure in parahippocampal and dorsal prefrontal cortices, regions which are known to be linked to attentional orienting to novel stimuli and perceptual processing of scenes. Novelty was also associated with activation of the substantia nigra/ventral tegmental area of the midbrain and the hippocampus, but these activations did not correlate with contextual memory enhancement. These findings indicate remarkable parallels between contextual memory enhancement in humans and existing evidence regarding contextually enhanced hippocampal plasticity in animals. They provide specific behavioral clues to enhancing hippocampus-dependent memory in humans.