Beta-hydroxybutyrate (D-BHB), a ketone body with neuroprotective properties, has been previously shown to increase the autophagic flux in neurons, but its effect on autophagy induction in astrocytes remains unexplored. Astrocyte functionality is essential for neuronal support, and this includes an optimal degradation and recycling of organelles and other cellular components through autophagy. The present study shows that D-BHB exposure to cultured astrocytes elevates the conjugated form of microtubule-associated protein 1A/1B-light chain 3 (LC3-II) levels, increases the number of autophagosomes, and reduces sequestosome-1 (SQSTM1/p62) protein content. D-BHB also enhanced the phosphorylation of AMP-activated kinase (AMPK) and Unc-51-like autophagy activating kinase 1 (ULK1), suggesting increased autophagy initiation. In addition, D-BHB induced the activation of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, increasing the abundance of the lysosomal-associated membrane protein 1 (LAMP1) and lysosomal number. Pharmacological inhibition of Sirtuin 1 (SIRT1) and AMPK/ULK1 activity abated D-BHB-induced increase in LC3-II and SQSTM1/p62 degradation, suggesting that D-BHB-mediated autophagy activation is dependent on the SIRT1/AMPK/ULK1 pathway. Also, results show that D-BHB induction of the autophagy-lysosomal axis improves astrocyte survival under oxygen-glucose deprivation (OGD). Together, the present data suggest that astrocytes, acting as targets of D-BHB, might contribute to the neuroprotective effects of ketone bodies against acute brain injury.