Myocardial infarction necessitates rapid reperfusion to limit ischemic damage. However, reperfusion itself exacerbates cardiomyocyte death and the inflammatory response. ATP release through pannexin1 (Panx1) channels is a key driver of leukocyte recruitment, yet most Panx1 channel inhibitors lack specificity or in vivo stability. We previously developed a macrocyclic peptidomimetic targeting the first extracellular loop (EL1) of Panx1, SBL-PX1-42, which demonstrated anti-inflammatory activity and high plasma stability in vitro. Here, we generated EL2 peptidomimetics, identified SBL-PX1-213 as a lead compound, and assessed its cardioprotective potential alone or combined with SBL-PX1-42 in experimental cardiac ischemia/reperfusion (I/R). In Langendorff-perfused wild-type (WT) hearts, SBL-PX1-42, SBL-PX1-213, and their combination did not affect baseline cardiac function, indicating absence of cardiotoxicity. In vivo I/R, induced by transient (30 min) coronary artery ligation and 24 h reperfusion, was performed in WT and Panx1^-/- mice. Intravenous administration of either compound at reperfusion reduced infarct size in WT animals. In Panx1^-/- mice, SBL-PX1-213 and the combination remained cardioprotective, whereas SBL-PX1-42 lost efficacy, supporting its Panx1-dependent activity. None of the treatments affected blood cell counts, suggesting the absence of unwanted side effects on circulating cells. These findings establish SBL-PX1-42 and SBL-PX1-213 as cardioprotective agents acting through both Panx1-dependent and Panx1-independent mechanisms.