Velvet antler is one of the most important animal medicines or functional foods widely used in East Asia for many centuries, which has several biological activities including anti-ageing and health promotion. To date, the mechanism underlying these effects of velvet antler is widely studied by its protein or polypeptide components. Few studies have been reported for the function of the other components in velvet antler. Herein, C. elegans is used as the model animal to dissect how none protein components of velvet antler affect in vivo oxidative stress. Methanol extracts (MEs) from velvet antler which has few protein components extends the maximum lifespan of C. elegans compared to the control under oxidative stress, while water extracts (WEs) which is protein-rich component has no apparent function. The activity of MEs is mediated by clk-1 signaling pathway, but not via daf-2, eat-2 or glp-1 pathway. Further investigations show MEs decrease endogenous ROS by promoting SKN-1 nuclei translocation, subsequently up-regulating the expression of its target genes gst-4, gst-7 and gst-10 in C. elegans. In all, MEs, the none protein components of velvet antler, protects against oxidative stress in C. elegans, which indicates it might be a product with potential of being a curative medicine.