MCL-1, an anti-apoptotic protein, is essential for the survival of various cell lineages and confers chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to mitochondrial metabolism, particularly long-chain fatty acid (FA) oxidation (FAO). This study reveals that MCL-1 supports essential steps in long-chain FAO through its interaction with specific long-chain acyl-CoA synthetases (ACSLs) of the ACSL family. Specifically, MCL-1 binds to ACSL1 via its BH3-binding pocket, a non-conventional BH3-domain. Disruption of this interaction, through genetic loss of *Mcl1*, mutagenesis, or selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and mouse tissues. The findings suggest that MCL-1 facilitates mitochondrial metabolism and that disruption of this function may explain the cardiac toxicities observed in clinical trials of MCL-1 inhibitors. The study also highlights the importance of understanding the non-apoptotic roles of anti-apoptotic BCL-2 family members to better manage their therapeutic applications.MCL-1, an anti-apoptotic protein, is essential for the survival of various cell lineages and confers chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to mitochondrial metabolism, particularly long-chain fatty acid (FA) oxidation (FAO). This study reveals that MCL-1 supports essential steps in long-chain FAO through its interaction with specific long-chain acyl-CoA synthetases (ACSLs) of the ACSL family. Specifically, MCL-1 binds to ACSL1 via its BH3-binding pocket, a non-conventional BH3-domain. Disruption of this interaction, through genetic loss of *Mcl1*, mutagenesis, or selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and mouse tissues. The findings suggest that MCL-1 facilitates mitochondrial metabolism and that disruption of this function may explain the cardiac toxicities observed in clinical trials of MCL-1 inhibitors. The study also highlights the importance of understanding the non-apoptotic roles of anti-apoptotic BCL-2 family members to better manage their therapeutic applications.