Acetaminophen (APAP) is the most popular mild analgesic and antipyretic drug used worldwide. APAP overdose leads to drug-induced hepatotoxicity and can cause hepatic failure if treatment delayed. It is adequately comprehended that the metabolism of high-dose APAP by cytochrome P450 enzymes generates N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite, which leads to glutathione (GSH) depletion, oxidative stress, and activation of various complex molecular pathways that initiate liver injury and downstream hepatic necrosis. Administration of activated charcoal followed by N-acetylcysteine (NAC) is considered the mainstay therapy; however, including side effects and limitation of rescuing for the delayed patients where liver transplantation may be a lifesaving procedure. Many complex signal transduction pathways such as c-Jun NH₂-terminal kinase (JNK), mammalian target of rapamycin (mTOR), nuclear factor (NF)-κB, and NF (erythroid-derived 2)- like 2 (Nrf2) are involved in the development of APAP hepatotoxicity, but yet hasn’t been comprehensively studied; thus, the search for effective antidotes and better management strategies continues. Here, we reviewed the most current advances to elucidate the etiological factors and therapeutic targets that could provide better strategies for the management of APAP-induced hepatotoxicity.