Background <p>Diethylnitrosamine (DEN) induces hepatic injury and can promote hepatocarcinogenesis. Quercetin (QR) and low-dose gamma irradiation (LDR) have been explored as hepatoprotective and anticancer-modulating agents, but their combined effects in DEN-induced liver cancer have not been previously examined.</p> Aim <p>To, for the first time, evaluate the novel combination of QR with LDR and compare its efficacy to QR or LDR alone in modulating DEN-induced liver cancer.</p> Methods <p>Hepatic injury was induced in ninety male rats by intraperitoneal DEN administration (75&#xa0;mg/kg weekly for 3 weeks, then 100&#xa0;mg/kg weekly for 3 weeks). After 6 weeks, hepatic injury establishment was confirmed histopathologically in a subset of rats. Animals were then randomized into five groups for an 8-week treatment period: (C) normal control; (DEN) no further treatment; (DEN + QR) quercetin (50&#xa0;mg/kg/day, oral); (DEN + IR) fractionated low-dose γ-irradiation (0.25&#xa0;Gy once weekly for 4 weeks, total 1&#xa0;Gy); (DEN + QR+IR) combined QR + IR. The total experimental duration was 14 weeks.</p> Results <p>DEN induced severe hepatotoxicity, with significantly elevated serum ALT and AST compared to controls (<i>p</i> &lt; 0.001). Markers of oxidative stress were markedly increased, while antioxidant enzymes and GSH were significantly reduced (<i>p</i> &lt; 0.001). DEN also led to substantial activation of inflammatory and growth signaling pathways, including NF-κB, STAT-3, mTOR, and p38 MAPK (<i>p</i> &lt; 0.001). Autophagy markers ULK-1, LC3-II, and ATG5 were significantly suppressed, and a pro-survival shift was evident with reduced caspase-3 activity and increased BCL-2 expression (<i>p</i> &lt; 0.001).Treatment with quercetin (DEN + QR) or low-dose γ-irradiation (DEN + IR) alone significantly mitigated these alterations versus DEN, restoring liver enzymes, reducing oxidative stress and inflammation, and promoting apoptotic signaling (<i>p</i> &lt; 0.001). The combination therapy (DEN + QR+IR) produced the most pronounced effects, with greater normalization of all biochemical and molecular parameters compared to DEN and to either monotherapy (<i>p</i> &lt; 0.001). These changes were statistically superior to those observed with quercetin or irradiation alone (<i>p</i> &lt; 0.01). Flow cytometry confirmed enhanced apoptosis and altered cell cycle dynamics in the combination group. Histopathological analysis showed markedly improved hepatic architecture and the lowest pathology scores with combination therapy (<i>p</i> &lt; 0.001 vs. DEN).</p> Conclusion <p>This study reveals, for the first time, a combined hepatoprotective effect of quercetin with low-dose gamma irradiation in DEN-induced liver pathology, suggesting new mechanistic insights and promising translational potential for combined therapy in DEN-associated liver injury and hepatocarcinogenesis.</p> Clinical Trial <p>This work isn’t a clinical Trial.</p> Graphical Abstract <p></p>