Resveratrol (RES) has been studied for its effects on the lifespan extension of Caenorhabditis elegans, but controversy still remains on its mechanism related with SIR-2. In this study, longevity assay was performed to confirm SIR-2-dependent lifespan extension of C. elgeans with RES and oxyresveratrol (OXY), an isomer of hydroxylated RES using loss-of-function mutants of C. elegans including sir-2.1 mutant. The results showed that OXY and RES significantly (P < 0.05) extended the lifespan of C. elegans compared with the control. OXY and RES also significantly (P < 0.05) increased the mRNA expression levels of sir-2.1 and aak-2 in a dose-dependent manner and increased the protein expression levels of SIR-2.1. OXY and RES treatment extended the lifespan in daf-16 loss-of-function mutants, which suggested that lifespan extension was not occurring via the activation of DAF-16. However, OXY and RES failed to extend the lifespan in loss-of-function mutants of sir-2.1 and aak-2 Therefore, OXY and RES extend the lifespan of C. elegans by overexpression of SIR-2.1, which is related to lifespan extension through calorie restriction and the AMP-activated protein kinase (AMPK) pathway, although this process is independent of the FOXO/DAF-16 pathway.