Yawning has been proposed to serve both physiological and social functions, the latter likely to have developed later in its evolution. A central hypothesis is that yawning cools the brain but whether yawning is a thermoregulatory mechanism that is activated during hyperthermia (i.e., thermoregulatory failure) or is activated in any instance of brain temperature increase (e.g., also during fever) is unclear and experimental assessments of yawning during fever are lacking. In this study, we determined the effect of experimentally induced fever on yawning frequency. We also explored alternative predictors of yawning during sickness (sleepiness, autonomic nervous system indexes and sickness symptoms). Twenty-two healthy human subjects participated in a randomized, placebo-controlled, cross-over study, where the subjects received an injection of the bacterial endotoxin lipopolysaccharide (LPS) at a dose of 2 ng/kg body weight in one condition and placebo in the other. Yawning was scored from video recordings from 30 min before to 4 h after the injection. Body temperature was measured frequently, alongside with heart rate, blood pressure, nausea and overall sickness symptoms. Yawning frequency was found to significantly increase over time during experimentally induced sickness, but not in the placebo condition. In particular, yawning frequency was increased during the rising phase of body temperature induced by LPS administration, although no significant correlation was found between body temperature increase and yawning frequency. In addition, exploratory analyses showed that a higher yawning frequency was associated with less increase in sickness symptoms and nausea intensity. While the current study adds to previous research showing significant increase in yawning frequency during hyperthermia, further studies are needed if we are to properly characterize the brain cooling role of yawning in humans. The investigation of other functions, such as being a vasovagal inhibitory, may shed stronger light on the functions of yawning.