Activity-dependent modulation of sensory systems has been documented in many organisms and is likely to be essential for appropriate processing of information during different behavioral states. However, the mechanisms underlying these phenomena remain poorly characterized. We investigated the role of octopamine neurons in the flight-dependent modulation observed in visual interneurons in Drosophila. The vertical system (VS) cells exhibit a boost in their response to visual motion during flight compared to quiescence. Pharmacological application of octopamine evokes responses in quiescent flies that mimic those observed during flight, and octopamine cells that project to the optic lobes increase in activity during flight. Using genetic tools to manipulate the activity of octopamine neurons, we find that they are both necessary and sufficient for the flight-induced visual boost. This study provides the first evidence that endogenous release of octopamine is involved in state-dependent modulation of visual interneurons in flies. ► Exogenously applied octopamine mimics flight effects in VS cells ► Octopamine neurons increase in activity during flight ► Octopamine neurons are necessary and sufficient to induce visual gain boost in VS cells