Circadian disturbances may lead to memory deficits and behavioral changes that are associated with a disrupted prefrontal cortex (PFC) to hippocampus (HIP) information flow in humans and in rodent models. Using a six-hour phase delay of the normal light-dark cycle to model an acute ‘jet-lag’ in mice, resulted in a reduced contextual fear memory. Neuronal activation, indicated by cFos immunohistochemistry, was increased in the hippocampal dentate gyrus (DG) and in the supramammillary nucleus (SUM), an important relay station for prefrontal-to-hippocampal information flow. Orexinergic neurons in the lateral hypothalamus were activated as well. Orexin is a wake-promoting neuropeptide targeting numerous brain regions relevant for memory and cognition. To investigate the potential modulation of the PFC-SUM-DG pathway by orexin, mRNA levels for orexin receptors were measured in laser microdissected neurons of the SUM, tagged by anterograde and retrograde viral tracers. SUM-to-DG projection neurons expressed low levels of the orexin receptor type 2 but not type 1 (OXR1). OXR1-positive PFC-to-DG relay cells in the SUM were then confirmed by a double tracing approach paired with immunohistochemistry. In the DG hilus, OXR1 was located in mossy cells, as demonstrated by RNAScope. Stimulating orexin receptors by intranasal application of orexin evoked a bimodal effect on contextual fear memory retrieval. Mice with different freezing levels showed differential in cFos activation signatures in the SUM, in DG mossy cells and in orexinergic neurons in the LH. Thus, orexinergic projections are well suited to modulate fear memory acting via the PFC-SUM-DG network, presumably on the internal state.