Functional peptides were obtained via enzymatic hydrolysis of smooth dogfish (Mustelus canis) skin. The enzyme-assisted process was optimized to achieve high yield of smooth dogfish skin peptides (SDSP). Fractions of SDSP (MW < 2 kDa, 2-5 kDa, 5-10 kDa and >10 kDa) showed in vitro antioxidant activities. The peptides <2 kDa (SDSP<2 kDa) significantly improved motility, reduced ROS and H2O2 levels of Caenorhabditis elegans, and increased its resistance to oxidative stress compared to the other peptide fractions. In vivo function of SDSP<2 kDa could be explained by their capacity to increase the expression of stress-response genes. The enhanced resistance to oxidative stress mediated by SDSP<2 kDa was dependent on DAF-16 and HSF-1. The amino acid residues and sequences of SDSP<2 kDa were characterized and revealed a higher content of hydrophobic versus polar amino acid contents. This study (especially the in vivo investigation) explored new potent antioxidant peptides derived from dogfish skin.