6PPD-quinone (6PPD-Q), a transformation product of the tire antioxidant 6PPD, is an emerging traffic-related contaminant with well-documented ecotoxicity in aquatic species. Its recent detection in airborne particulate matter, road dust, and human urine has raised concern about possible human health effects, yet its cardiotoxicity in mammals remains poorly understood. Here, we integrated network toxicology, molecular modeling, and in vitro experiments to investigate the effects of 6PPD-Q on human AC16 cardiomyocytes and the underlying mechanisms. Network toxicology identified 144 putative targets associated with 6PPD-Q-induced cardiotoxicity, with TP53 ranked as the top hub, followed by TRAF6, MAPK1, SQSTM1, TNF, and IL6. Enrichment analysis highlighted oxidative stress, inflammation, apoptosis, and autophagy regulation as key biological processes. Molecular docking predicted favorable binding of 6PPD-Q to all six hub proteins, while molecular dynamics simulations supported a stable interaction with p53. Experimentally, 6PPD-Q (IC50 = 13.92 μM) induced marked ROS accumulation in AC16 cells. It also promoted p53 phosphorylation at Ser15 without increasing total p53 protein or mRNA, indicating post-translational activation. This was accompanied by TRAF6 upregulation, enhanced MAPK1 phosphorylation, and increased IL6 and TNF expression, supporting involvement of a p53/TRAF6/MAPK1-associated inflammatory response. Functionally, 6PPD-Q triggered mitochondrial apoptosis, as indicated by an increased Bax/Bcl-2 ratio and cleaved caspase-3/9, and disrupted autophagy homeostasis, as evidenced by LC3-II accumulation and SQSTM1/p62 depletion. Collectively, these findings show that 6PPD-Q induces cardiomyocyte injury through a p53-centered stress network linking oxidative stress, inflammation, apoptosis, and autophagic dysfunction, providing mechanistic insight into its potential cardiovascular risk.