Acute pancreatitis (AP) is an inflammatory disease that is associated with trypsinogen activation, mitochondrial dysfunction, cell death, and inflammation. Dopamine D2 receptor (DRD2) plays an essential role in alleviating AP, while it is unclear whether it is involved in regulating acinar cell necroptosis. Here, we found that DRD2 agonist quinpirole alleviated acinar cell necroptosis via inhibiting cathepsin B (CTSB). Moreover, CTSB inhibition by CA-074Me ameliorated AP severity by reducing necroptosis. Notably, knockdown of TFAM reversed the therapeutic effect of either quinpirole or CA-074Me. We identified a new mechanism that DRD2 signaling inhibited CTSB and promoted the expression of mitochondrial transcription factor A(TFAM), leading to reduction of ROS production in AP, which attenuated acinar cell necroptosis ultimately. Collectively, our findings provide new evidence that DRD2 agonist could be a new potential therapeutic strategy for AP treatment.