Phyllanthus amarus is a medicinal plant with immense benefits. Several experimental investigations have explored and establish its phytochemical constituents. This study was carried out to evaluate the antioxidant potentials and inhibitory effects of the hydro-alcoholic extract of the leaves on two major enzymes involved in the hydrolysis of extracellular ATP- Nucleoside triphosphate diphosphohydrolase (NTPDases) and 5?-nucleotidase in rat tissues using in-vitro models. The extract shows a dose dependent scavenging abilities against free radicals such as 2,2 diphenyl-2-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), hydroxyl radical, superoxide radical, and nitric oxide(NO) radicals. The ferric reducing power, Vitamin C content and total phenol content also increases as the concentration increases. The extract of Phyllanthus amarus showed significant inhibition (P< 0.05) of NTPDase and 5?-nucleotidase enzymes in rat tissues with increasing concentrations. Research has shown that targeting these purinergic enzymes could be a novel target for cancer immunotherapy and have been projected to be valuable tools in clinical therapeutics such as in the treatment of chronic pain, immune system diseases and cancer, as they would prolong the physiological effects of extracellular nucleotides or simultaneously administered nucleotide analogues. The hydro- alcoholic extract of Phyllanthus amarus with its high radical scavenging ability and inhibitory effects on the purinergic enzymes could be explored in the treatment of chronic pain, cancer and immune system related diseases.