The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAKalpha senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAKalpha activation. Underscoring the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAKalpha kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet exhibit ZAKalpha-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing high-fat diet-induced blood glucose intolerance and liver steatosis under these conditions. Finally, ZAK ablation slows animals from developing hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAKalpha that underlies metabolic adaptation in obesity and aging.