Acetaminophen (APAP) is a popularly utilized nonprescription antipyretic and analgesic medication. Overuse of APAP could result in serious liver damage, threatening human health and escalating fatality rates. Catechin is a polyphenolic flavonoid with robust antioxidative and anti-inflammatory capacities. This experiment was intended to assess the possible protective effect of catechin versus acetaminophen-exacerbated liver injury in a rat model. Twenty-four rats were allocated into four groups with six rats each. The control group obtained normal-saline orally for 7 days. The acetaminophen group was given a single dosage of APAP (2 gm/kg) orally on the 7th day. The catechin + APAP group got catechin (50 mg/kg intraperitoneally) once a day for 7 days, followed by an APAP dosage on the 7th day. Catechin effectively mitigated the degree of APAP-evoked liver injury by downregulating acetaminophen-aggravated elevation of hepatic biochemical indicators such as ALT, AST, and TSB, as well as rectifying histological abnormalities. Additionally, catechin administration to APAP-exposed rats profoundly lowered the contents of oxidative factors like malondialdehyde (MDA) while strengthening the activity of antioxidative molecules, particularly GSH and SOD, in liver tissues. Catechin also dramatically minimized hepatic tissue amounts of pro-inflammatory substances, including IL-8, IL-17, and TNF-α. In conclusion, catechin could protect against acetaminophen-induced liver damage, most likely due to its strong anti-inflammatory, anti-oxidative, and antiangiogenic abilities.