D-β-hydroxybutyrate, BHB, has been previously proposed as an anti-senescent agent in vitro and in vivo in several tissues including vascular smooth muscle. Moreover, BHB derivatives as ketone esters alleviate heart failure. Here, we provide evidence of the potential therapeutic effect of BHB on Hutchinson-Gilford progeria syndrome (HGPS), a rare condition characterized by premature aging and heart failure, caused by the presence of progerin, the aberrant protein derived from LMNA/C gene c.1824C > T mutation. We have assessed several hallmarks of HGPS-senescent phenotype in vitro, such as progerin levels, nuclear morphometric aberrations, nucleolar expansion, cellular senescent morphology, SA-βGal-positive cells, H3K9me3 heterochromatin, γH2AX foci, Lamin B1, p21 and p16 abundance, and autophagy. Strikingly, BHB improved nuclear and nucleolar morphometrics, diminished the senescence-phenotype, and unstuck autophagy in HGPS as observed by an enhanced degradation of the cargo protein receptor SQSTM1/p62, suggesting the stimulation of the autophagic flux. Additionally, we observed a decrease in progerin abundance, the cause of senescence in HGPS. Furthermore, compound C, an inhibitor of AMPK, and SBI-0206965, an inhibitor of ULK1/2 and AMPK, which prevent autophagy activation, reversed BHB-induced progerin decline as well as its anti-senescent effect in an AMPK-mTORC1 dependent manner. Altogether, these results suggest that the anti-senescence effect of BHB involves progerin clearance by autophagy activation supporting the potential of BHB for HGPS therapeutics and further preclinical trials.