N-acetylcysteine (NAC) is the definitive antidote for paracetamol overdose because it replenishes hepatic glutathione stores, allowing safe metabolism of the toxic metabolite NAPQI. Without NAC, NAPQI accumulates and causes severe hepatocellular injury. Early administration (ideally within 8 hours) significantly reduces liver damage and improves patient outcomes. NAC also has antioxidant and anti-inflammatory properties that protect liver cells. This makes it the primary treatment, unlike options that only limit absorption or treat unrelated toxicities.

Reference: Harrison's Principles of Internal Medicine, Kasper et al., 20th Edition.