N(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPDQ) is an emerging pollutant generated via environmental oxidation of tire-derived 6PPD. Although concerns have been raised about its potential toxicity, the organ-specific and cross-organ toxicological mechanisms in mammalian liver and kidney remain poorly understood. This study aimed to investigate the toxic mechanisms of 6PPDQ in the liver and kidney of mice, with a focus on elucidating both organ-specific damage and correlations in cross-organ toxicity. Using network toxicology and molecular docking, we predicted potential targets related to 6PPDQ-induced hepatotoxicity and nephrotoxicity. Histopathological analysis confirmed that 6PPDQ causes abnormal antioxidant levels, hepatic inflammation, and renal tissue edema. Integrated transcriptomic and metabolomic analyses revealed that 6PPDQ disrupts arachidonic acid metabolism in the liver and induces abnormal arginine metabolism and osmoregulatory dysfunction in the kidney. Through western blot and qPCR assays, we further validated p53 and Fos as key cross-organ targets and identified arginine biosynthesis and related pathways as common metabolic mechanisms. This study provides novel insights into the mechanisms of 6PPDQ-induced liver and kidney injury and contributes to the development of organ-specific and cross-organ biomarkers for toxicity caused by environmental pollutants.