The sodium–calcium exchanger (NCX) is a critical mediator of calcium homeostasis. In the heart, NCX1 predominantly operates in forward mode to extrude Ca²⁺; however, reverse‐mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca²⁺ loading and electrical and contractile dysfunction. IR injury has also been associated with altered fat metabolism and accumulation of long‐chain acyl CoA esters. Here, we show that acyl CoAs are novel, endogenous activators of reverse‐mode NCX1 activity, exhibiting chain length and saturation dependence, with longer chain saturated acyl moieties being the most effective NCX1 activators. These results implicate dietary fat composition as a plausible determinant of IR injury. We further show that acyl CoAs may interact directly with the XIP (exchanger inhibitory peptide) sequence, a known region of anionic lipid modulation, to dynamically regulate NCX1 activity and Ca²⁺ homeostasis. Additionally, our findings have broad implications for the coupling of Ca²⁺ homeostasis to fat metabolism in a variety of tissues.