Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic agents for the management of mild to moderate pain. Though clinically safe at therapeutic doses, excessive use causes severe toxicity due to reactive metabolites inducing oxidative stress and hepatotoxicity. Sideritis congesta, has been traditionally utilized for its anti-inflammatory, anti-ulcer, antioxidant, and antimicrobial properties. In the present study, we aimed to investigate the potential protective effects of S. congesta aqueous and hydroalcoholic extract against APAP-induced cytotoxicity and oxidative stress in HepG2 cell line. The anti-inflammatory and anti-mutagenic activities of S. congesta AE has been evaluated. Moreover, bioactive compounds were further analyzed using in silico methodologies to predict biological activities. Our findings revealed that APAP treatment significantly reduced SOD and CAT activity along with GSH level, whereas pretreatment with S.congesta extracts effectively restored their activities. Additionally, APAP-induced elevated MDA levels, was significantly mitigated by S. congesta extracts. Moreover, its extracts demonstrated potent antimutagenic activity. These findings show that S. congesta has strong hepatoprotective effects against APAP-induced oxidative stress and cytotoxicity. Its ability to modulate antioxidant defense systems, inhibit lipid peroxidation, and exert anti-inflammatory and anti-mutagenic effects underscores its potential as a natural therapeutic candidate for mitigating APAP-induced toxicity.