Abstract Iron overload and cellular senescence have been implicated in liver fibrosis, but their possible mechanistic connection has not been explored. To address this, we have deepened into the role of iron and senescence in an experimental model of chronic liver injury, analyzing whether an iron chelator would prevent liver fibrosis by decreasing hepatocyte senescence. The model of carbon tetrachloride (CCl4) in mice was used as experimental model of liver fibrosis. Results demonstrated that during the progression of liver fibrosis, accumulation of iron occurs, concomitant with the appearance of fibrotic areas and senescent cells surrounding these areas. Isolated parenchymal hepatocytes from CCl4-treated mice show a gene transcriptomic signature compatible with iron accumulation and senescence, which correlate with induction of Reactive Oxygen Species (ROS)-related genes and activation of the Transforming Growth Factor-beta (TGF-β) pathway. Analysis of the iron-related gene signature in a published single-cell RNA-seq dataset from CCl4-treated livers indicated iron accumulation also in other non-parenchymal liver cells, correlating with senescence in some of them. Treatment with deferiprone, an iron chelator, attenuated the accumulation of iron, fibrosis and senescence, concomitant with relevant changes in the senescent-associated secretome (SASP), which switched towards a more anti-inflammatory profile of cytokines. In vitro experiments in human hepatocyte HH4 cells demonstrated that iron accumulates in response to a senescence inducing reagent, doxorubicin, being deferiprone able to prevent senescence and SASP, attenuating growth arrest and cell death. However, deferiprone did not significantly affect senescence or activation markers in human hepatic stellate LX-2 cells. Transcriptomic data in patients demonstrated the relevance of iron accumulation in the progression of liver fibrosis, correlating with a SASP-related gene signature and pivotal hallmarks of hepatocyte damage. Altogether, our study establishes iron accumulation as a clinically exploitable driver to attenuate pathological senescence in hepatocytes.