Heat stress (HS) is devastating to poultry production worldwide, yet its biology and molecular responses are not well defned. Although advances in management strategy have partially alleviated the negative impact of HS, productivity still continues to decline when the ambient temperature rises. Therefore, identifying mechanism-based approaches to decrease HS susceptibility while improving production traits is critical. Recently, we made a breakthrough by applying a surface wetting strategy and showing that it improves growth performance compared with the current conventional cooling system. In the present study, we aimed to further defne molecular mechanisms associated with surface wetting in ameliorating HS productivity loss in broilers. Five-week-old broiler chickens were exposed to acute HS (35°C for 2 h) alone or in combination with surface wetting. A control group was maintained at thermoneutral conditions (25°C). Core body temperature (BT) and feed intake were recorded. Blood was collected and hypothalamic tissues (main site involved in the regulation of energy homeostasis) were harvested to determine the expression profle of stress- and metabolic-related genes. Surface wetting prevents HS from increasing BT and plasma corticosterone levels (P < 0.05) and improves feeding and drinking behaviors. At molecular levels, surface wetting blocks the activation of hypothalamic heat shock protein and adenosine monophosphate-activated protein-induced by HS and signifcantly modulates the expression of feeding-related hypothalamic neuropeptides (agouti-related protein, proopiomelanocortin, orexin, orexin receptor, and leptin receptor). Taken together, our data represent the frst evidence that surface wetting alleviates systemic and intracellular stress induced by HS and preserves the intracellular energy status, which, in turn, may result in improved broiler well-being and growth performance.