Non‐technical summary Systemic inflammation and related disorders, including sepsis, are leading causes of death in hospitalized patients. In most severe cases, systemic inflammation is accompanied by a drop in body temperature (hypothermia). We know that inflammation‐associated hypothermia is a brain‐mediated response, but mechanisms of this response are unknown. We administered a bacterial product (endotoxin) to rats to cause systemic inflammation and hypothermia. We then used a variety of pharmacological tools to probe whether three different receptors are involved in this hypothermia. We have found that one of the receptors studied, the so‐called cannabinoid‐1 (CB1) receptor, is crucial for the development of hypothermia. This is the same receptor that is responsible for many effects of marihuana (cannabis). We further show that hypothermia associated with inflammation depends on CB1 receptors located inside the brain. These novel findings suggest that brain CB1 receptors should be studied as potential therapeutic targets in systemic inflammation and sepsis.