This study was to investigate invivo and invitro hepatoprotective role of Indian earthworm (Pheretima posthuma) protein powder (EP) in rats against paracetamol induced liver damage. Briefly, the animals were divided into 4 groups (n=6) of wister albino male rats. Normal group, 1 ml of 20% Tween 80 (vehicle) was administered orally for 2 days in a week for 14 days. Paracetamol-treated group, paracetamol (750 mg/kg p.o.) suspension was administered orally twice a week for 14 days. Paracetamol-EP treated group, paracetamol suspension was administered concurrently with EP (266 mg/kg b.w), orally twice a week for 14 days. Paracetamol and silymarin treated group, paracetamol suspension was administered concurrently with silymarin (100 mg/kg p.o.) orally twice a week for 14 days. Paracetamol–treated animals exhibited a significant (P<0.05) elevation of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, LPO or MDA, total bilirubin, mRNA expressions of TNF- α and IL-6 while the level of CAT, SOD, GSH significantly (P<0.05) decreased in the paracetamol group and was later restored in paracetamol-EP treated group. Similarly, the separated MWCO 50 KDa protein obtained from EP (lyophilized) using Sephadex-G75 showed significant (P<0.05) reduction of AST and ALT, ALP and bilirubin in primary hepatocyte culture supernatant and increased percentage viability. The histological examination of paracetamol group showed disruption of the liver histoarchitecture and its restoration was found in the paracetamol-EP group. The invivo study, showed that the animals in the paracetamol-EP and the paracetamol-silymarin groups showed restoration of biochemical parameters, oxidative stress markers, mRNA expressions and histopathological findings. The acute liver damage due to paracetamol is attributed to the oxidative stress in the animal model. EP decreased oxidative stress as well as inflammation and slowed down the liver damage progression caused by paracetamol. EP (Pheretima posthuma) activities involving cytokine expressions e.g., TNF-α and IL-6 using lower molecular weight protein fraction from the dialysate i.e., MWCO 50 kDa and below protein fractions is of scientific importance with correlation to real time use.