Ageing is a complex but universal phenomenon that progressively challenges the homeostasis network and finally leads to the dysfunction of organisms and even death. Previous studies demonstrated that xyloketal B and its derivatives, a series of marine novel ketone compounds, possessed unique antioxidative effects on endothelial and neuronal oxidative injuries. In this study, we examined the effects of xyloketal derivatives on extending lifespan and healthspan of Caenorhabditis elegans. The results showed that most selected xyloketals could protect Caenorhabditis elegans against heat stress and extend the lifespan of worms. Compound 15, a benzo-1, 3-oxazine xyloketal derivative, possessed most potent effect in anti-heat stress assay and significantly attenuated ageing-related decrease of pumping and bending of the worms in healthspan assay. In addition, the beneficial effect of 15 was abolished in PS3551 worms, a strain that possesses non-functional heat shock transcription factor-1 (HSF-1). Furthermore, 15 increased the expression of heat shock protein 70 (HSP70), a downstream molecular chaperone of HSF-1. These results indicated that HSF-1 might contribute to the protective effect of this compound in Caenorhabditis elegans ageing. Molecular docking studies suggested that these xyloketal derivatives were bound to the DNA binding domain of HSF-1, promoted the conformation of HSF-1, thus strengthened the interaction between the HSF-1 and related DNA. ALA-67, ASN-74 and LYS-80 of binding region might be the key amino residues during the interaction. Finally, compound 15 could reduce the paralysis of the CL4176 worms, a transgenic strain expressing human Aβ3-42 under a temperature-inducible system. Collectively, these data indicate that xyloketals have potential implications for further evaluation in anti-ageing studies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.