Background <p>Doxorubicin (DOX) has long been a foundational drug in cancer therapeutics. Despite its proven efficacy, the persistent challenge of mitigating its associated side effects, notably hepatotoxicity and neurotoxicity, underscores the necessity for intervention. Luteolin (LUT) is a naturally derived flavonoid with a spectrum of bioactive characteristics, involving anti-apoptotic, antioxidant, anti-inflammatory, and anti-cancer attributes. This study investigates the possible protective effect of LUT against DOX-induced hepatotoxicity and neurotoxicity, focusing on its modulation of the endoplasmic reticulum (ER) stress pathways and miRNA 199a- 5p expression. Forty-eight male Sprague Dawley rats were assigned to six groups: control, LUT (200 mg/kg), DOX (3.5 mg/kg, i.p.) administered twice per week for 3&#xa0;weeks, and three treatment groups that received daily oral gavage of LUT at doses of 50, 100, and 200 mg/kg for 3&#xa0;weeks alongside DOX.</p> Results <p>Behavioral assessments revealed the best improvements in rats co-treated with LUT high dose (200 mg/kg), paralleled by the mitigation of neurodegeneration in the cortex and hippocampal areas of the brain. The hepatoprotective effect of LUT (200 mg/kg) demonstrated a notable decrease in liver enzymes and restoration of hepatocytic architecture, coupled with upregulation of&#xa0;miRNA-199a-5p and suppression of glucose-regulated protein 78 (GRP78). LUT inhibited ER stress via suppressing the inositol-requiring enzyme 1 alpha (IRE1α)/protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/activating transcription factor 6 (ATF6) axes, thereby inhibiting apoptosis.</p> Conclusions <p>LUT 200 mg/kg is efficacious in alleviating DOX-induced hepatic injury and neurotoxicity via dampening ER stress pathways.</p> Graphical abstract <p></p>