BACKGROUND: Paracetamol (PAC) overdose causes acute liver injury through oxidative stress, inflammation, and apoptosis. While N-acetyl cysteine (NAC) is the standard treatment, fucoxanthin (FUC), a carotenoid from brown seaweed, has shown hepatoprotective effects in animal studies, but its role in PAC toxicity is unclear. OBJECTIVE: Compared to NAC, this study assessed the hepatoprotective potential of oral FUC solution towards PAC-induced injury to the rat's liver. METHOD: FUC was formulated as a pharmaceutical solution and characterized via UV-VIS spectroscopy. Six groups of male Wistar rats each contain five animal which are in total thirty rats: negative control (NC), positive control (PC, 2 g/kg PAC), NAC (1200 mg/kg), and three oral FUC doses (100, 200, and 500 mg/kg) for seven days, with PAC administered on day-8. Liver tissues were analyzed for oxidative stress, gene expression, and histology. RESULTS: FUC solution was clear with absorbance at 433 nm. PAC caused 30% mortality (p <
0.01 vs. others). NAC reduced ALT (56%), AST (78%), ALP (28%), and increased TP by 25% (p <
0.001 vs. PC). FUC at 500 mg/kg (F500) was superior, reducing ALT (82%), AST (93%), ALP (40%), and increasing TP (35%) (p <
0.001 vs. NAC). PAC increased oxidative stress, CYP2E1/CYP3A2 expression, apoptosis markers, and suppressed Nrf2/AMPK/AKT1. F500 improved antioxidants, reduced oxidative stress, and apoptosis, enhanced the Nrf2/AMPK pathway, and downregulated CYP2E1/CYP3A2 (p <
0.01). CONCLUSION: FUC, particularly at 500 mg/kg, offers significant hepatoprotection against PAC-induced liver injury by modulating drug metabolizing enzymes and enhancing antioxidant defences, warranting further research.