Echinacoside is one of the phenylethanoids isolated from the stems of Cistanches salsa. Our previous research showed that echinacoside has anti-senescence activity. To investigate the mechanism of echinacoside's anti-senescence activity, the expressions of p53, p21, p16 and Rb at the mRNA and protein levels were determined. Results showed that the expression of p53 was down-regulated significantly in a dose dependent manner after treatment with echinacoside. Further experiments suggested that the down-regulation of p53 may be correlated with the upregulation of SIRT1. In addition, echinacoside may exhibit considerable higher affinity towards SIRT1 than resveratrol, according to our molecular docking simulation. In conclusion, we expect that echinacoside might be a promising candidate for regulating cell senescence.