Symptoms of anxiety are usually induced by sensory stimuli, but the contribution of sensory system deficits to anxiety disorders remains unknown. Here, mice with mutation-induced functional deficits in the main olfactory epithelium (MOE) — one of the two sensory organs that comprise the mouse olfactory system (the other being the vomeronasal organ (VNO)) — exhibited increased levels of anxiety-like behaviour in three behavioural paradigms. Mice expressing the M71 odorant receptor in ∼95% of MOE and VNO neurons have impaired odour-evoked neural activity and also showed increased anxiety in these tests. Thus, the olfactory system is a key modulator of anxiety in mice.