Abstract Organophosphorus compounds are acetylcholinesterase inhibitors used as pesticides and chemical warfare nerve agents. Acute organophosphorus poisoning (acute OPP) affects 3 million people, with 300 000 deaths annually worldwide. Severe acute OPP effects include overstimulation of cholinergic neurons, seizures, status epilepticus, and finally, brain damage. In a previous study, we developed 3 different chemical models of acute OPP in zebrafish larvae. To elucidate the complex pathophysiological pathways related to acute OPP, we used integrative omics (proteomic, transcriptomics, and metabolomics) on these 3 animal models. Our results show that these stochastic, apparently disparate morphological phenotypes can result from almost linear concentration-response variations in molecular levels. Results from the multiomics analysis strongly suggest that endoplasmic reticulum stress might play a central role in the pathophysiology of severe acute OPP, emphasizing the urgent need of further research on this molecular pathway. Endoplasmic reticulum stress could be an important therapeutic target to be included in the treatment of patients with severe acute OPP.