Lipid metabolism is a key process required for muscle stem cell (MuSCs) function during regenerative myogenesis. However, the molecular pathway responsible of such regulation is still unknown. Studies of lysine demethylase PHF2 have reported its critical role in lipid metabolism in pathological processes, although there are no data regarding its role during MuSC fate. Here we identify PHF2 as a key regulator of lipid droplet homeostasis in MuSCs during regenerative myogenesis, by promoting lipid droplets/mitochondria contacts. Consistently, in absence of PHF2, myocytes accumulate lipid droplets, leading to impaired regeneration. Interestingly, such phenotype is rescued by overexpressing AMPKα2-PHF2 phospho-mimetic mutant. Mechanistically, we show that PHF2 acts as a transcriptional repressor by recruiting the complex RUNX2 and SIN3A on the Gdi2 gene locus to suppress its expression. This repression is necessary for RAB8a activation and recruitment to mitochondria thereby facilitating lipid droplet turnover. Together, our findings establish PHF2 as a critical effector of the AMPKα2/PHF2/Gdi2 axis, coupling transcriptional repression with organelle communication to regulate lipid metabolism during regenerative myogenesis.