The mammalian retina is considered an autonomous neuronal tissue, yet there is evidence that it receives inputs from the brain in the form of retinopetal axons. A sub-population of these axons was suggested to belong to histaminergic neurons located in the tuberomammillary nucleus (TMN) of the hypothalamus. We identified these retinopetal axons and found that although few in number, they extensively branch to cover a large portion of the retina. Using Ca2+ imaging and electrophysiology, we revealed how histamine application, as well as a direct activation of the retinopetal axons, modulate activity of retinal ganglion cells. Finally, we found that in humans, an antihistamine non-uniformly modulates visual sensitivity across the visual field. Since TMN activity was shown to correlate with arousal state, our data suggest that the retinal code changes with behavioral state through the release of histamine from TMN neurons.