Although it is known that the accumulation of methylglyoxal (MGO) and advanced glycosylation end products (AGEs) results in oxidative injury, the comparison between caffeic acid (CA) and chlorogenic acid (CGA) against oxidative damage remains unclear. Therefore, this study was conducted to compare the effects of CA and CGA using PC12 cells and Caenorhabditis elegans. The antioxidant regulatory targets for CA and CGA were primarily detected in the NRF2 pathway as predicted by network pharmacology. First, CA exerted higher effects than CGA in increasing cell viability and mitochondrial membrane potential, reducing ROS production and apoptosis, and promoting the expression of NRF2 translocation and downstream genes, which were consistent with the results of molecular docking, molecular dynamics, and covariance matrix simulations. Second, treatment with ML385 (Nrf2 inhibitor) eliminated the anti-cytotoxic effect and ROS accumulation reduction effect of CA and CGA. Third, CA exhibited stronger capacities in extending lifespan, inhibiting ROS production, and increasing SKN-1 proportion than CGA in C. elegans. Multi-spectroscopy analysis also revealed a stronger inhibitory effect of CA on the formation of AGEs than that of CGA, which might be related to the alteration of the protein α-helix. Therefore, considering the higher antioxidant effects of CA, it can be used as a promising antioxidant natural drug resource.