Lactucaserriola (L. serriola), commonly known asprickly lettuce, is an annual and biennial herb. The plant is traditionally used as sedative, hypnotic, cough suppressant, expectorant, purgative, diuretic, vasorelaxant, demulcent, antiseptic and antispasmodic. Aim of present study was to evaluate protective effect of L. serriola in paracetamol-induced hepatotoxicity. Silymarin was used as a standard drug. Hepatoprotective effect of extract was determined by liver biochemical markers, anti-oxidant enzymes and blood lipid profile. Methanolic extract was found to be the most potent in in-vitro antioxidant assays and used for further studies. Treatment with paracetamol increased the level of hepatic biomarkers, blood lipid profile and decreased anti-oxidant enzyme levels. Pre-treatment with Lactuca serriola caused restoration of hepatic biomarkers, blood lipid profile and antioxidant enzymes. FTIR represented that L. serriola contains hydroxyl (-OH), carboxylic acid (C=O) and alkene (C=C) groups. HPLC analysis showed presence of polyphenolic compounds in the methanolic extract of L. serriola. It is concluded that the methanolic extract of Lactuca serriola possesses hepatoprotective potential that might be linked to the presence of polyphenolic compounds and their anti-oxidant activities.