AbstractToxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose‐conjugated hydroxyl polyamidoamine dendrimer (D4‐Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)‐induced liver failure. D4‐Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non‐Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4‐Gal conjugated toN‐acetyl cysteine (NAC) was tested in a mouse model of APAP‐induced liver failure. A single intravenous dose of a conjugate of D4‐Gal and NAC (Gal‐d‐NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4‐Gal is effective in targeting and delivering therapies to hepatocytes and Gal‐D‐NAC has the potential to salvage and treat liver injury with a broader therapeutic window.