Acidosis is a common characteristic of brain damage. Because studies have shown that permeable Ca-acid-sensing ion channels can mediate the toxic effects of calcium ions, they have become new targets against pain and various intracranial diseases. However, the mechanism associated with expression of these channels remains unclear. This study sought to observe the expression characteristics of permeable Ca-acid-sensing ion channels during different reperfusion inflows in rats after cerebral ischemia. The rat models were randomly divided into three groups: adaptive ischemia/reperfusion group, one-time ischemia/reperfusion group, and severe cerebral ischemic injury group. Western blot assays and immunofluorescence staining results exhibited that when compared with the one-time ischemia/reperfusion group, acid-sensing ion channel 3 and Bcl-x/l expression decreased in the adaptive ischemia/reperfusion group. Calmodulin expression was lowest in the adaptive ischemia/reperfusion group. Following adaptive reperfusion, common carotid artery flow was close to normal, and the pH value improved. Results verified that adaptive reperfusion following cerebral ischemia can suppress acid-sensing ion channel 3 expression, significantly reduce Ca influx, inhibit calcium overload, and diminish Ca toxicity. The effects of adaptive ischemia/reperfusion on suppressing cell apoptosis and relieving brain damage were better than that of one-time ischemia/reperfusion. RESEARCH HIGHLIGHTS: (1) Acidosis is a common characteristic of brain damage. Recent studies have confirmed that the decrease in extracellular pH can activate acid-sensing ion channels that are widely distributed in the body, but the precise mechanism remains unclear.(2) This study observed the characteristics of acid-sensing ion channel 3 expression and the distribution of calmodulin following different reperfusion flows. We revealed a relationship between acidosis, calcium overload and cell apoptosis following ischemia/reperfusion injury in the rat brain.(3) This study used adaptive reperfusion to restore cerebral blood flow following cerebral ischemia. Our results confirmed that adaptive reperfusion has slight effects on brain damage.(4) Adaptive ischemia/reperfusion inhibited acid-sensing ion channel 3 expression, and its effects on suppressing cell apoptosis and relieving brain damage were better than that of one-time ischemia/reperfusion.