Due to its widespread availability, acetaminophen (APAP) is the leading cause for drug-induced liver injury in many countries including United States and United Kingdom. When used as recommended, APAP is relatively safe. However, in overdose cases, increased metabolism of APAP to N-acetyl-para-benzoquinoneimine (NAPQI), a reactive metabolite, leads to glutathione (GSH) depletion, oxidative stress, and cellular injury. Throughout this process, a variety of factors play important roles in propagating toxicity, including c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family. Because of its involvement in multiple cellular processes, biomarkers associated with MAPK signaling have generated interest as a mechanistic target for protecting against APAP-induced liver injury and hepatocellular injury, in general. This review summarizes mechanistic details by which natural products, specifically those containing polyphenolic moieties, are capable of attenuating APAP-induced toxicity, at least in part through an ability to modulate MAPKs. These compounds include carnosic acid, chlorogenic acid, davallialactone, extracts from Hibiscus sabdariffa, quercetin-based compounds, and resveratrol. Despite variations in the experimental designs across these studies, common pathways and biomarkers were implicated in cytoprotection when polyphenolic compounds were given with APAP, such as enhanced antioxidant gene expression and reversal of APAP-induced changes in oxidative stress markers and MAPK signaling. Overall, an emphasis should be placed on method standardization for future studies if we are to gain a more in-depth understanding of how polyphenolic moieties contribute to cytoprotection during an APAP overdose event.