SIRT6 is a NAD(+)-dependent deacetylase that modulates chromatin structure and safeguards genomic stability. So far, SIRT6 has been assigned to the nucleus and only nuclear targets of SIRT6 are known. Here, we demonstrate that in response to stress, C. elegans SIR-2.4 and its mammalian orthologue SIRT6 localize to cytoplasmic stress granules (SGs), interact with various SGs components and induce their assembly. Loss of SIRT6 or inhibition of its catalytic activity in MEF cells impairs SGs formation and delays disassembly during recovery, while deficiency of SIR-2.4 diminishes maintenance of P granules and decreases survival of C. elegans under stress condition.Our findings uncover a novel, evolutionary conserved function of SIRT6 in maintenance of SGs in response to stress.