Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Here, we elucidate a transcellular signaling mechanism by which oligodendrocytes support axonal energy metabolism via transcellular delivery of NAD-dependent deacetylase SIRT2. SIRT2 is undetectable in neurons but enriched in oligodendrocytes and released within exosomes. By deleting sirt2, knocking down SIRT2, or blocking exosome release, we demonstrate that transcellular delivery of SIRT2 is critical for axonal energy enhancement. Mass spectrometry and acetylation analyses indicate that neurons treated with oligodendrocyte-conditioned media from WT, but not sirt2-knockout, mice exhibit strong deacetylation of mitochondrial adenine nucleotide translocases 1 and 2 (ANT1/2). In vivo delivery of SIRT2-filled exosomes into myelinated axons rescues mitochondrial integrity in sirt2-knockout mouse spinal cords. Thus, our study reveals an oligodendrocyte-to-axon delivery of SIRT2, which enhances ATP production by deacetylating mitochondrial proteins, providing a target for boosting axonal bioenergetic metabolism in neurological disorders. Display omitted •Oligodendrocyte-to-neuron signaling enhances axonal mitochondria ATP production•Elevating neuronal deacetylase SIRT2 facilitates mitochondria ATP production•SIRT2 is transcellularly delivered from oligodendrocytes to axons via exosomes•In vivo delivery of OL-EXOs rescues axonal mitochondrial integrity in spinal cords Neurons require mechanisms to maintain axonal ATP. Chamberlain et al. identify an exosome-mediated transcellular pathway through which oligodendrocyte-derived sirtuin 2 is delivered to axons, enhancing bioenergetics by deacetylation of mitochondrial proteins for increased ATP generation. Revealing this pathway advances understanding of axonal energy maintenance in health and neurological disorders.