The ethanol extract of Tragia involucrata (TME) whole plant was evaluated for its antitumor potential using in vitro as well as in vivo lymphoma models. The antiproliferative potential of the extract was revealed in the in vitro assay performed using YAC-1 cells. The number of live cells reduced from 10.25 × 10 4 to 1.0 × 10 4 after 48 h of treatment with 15 μg/mL of TME, and the untreated control cells multiplied to reach 15.0 × 10 4 in number by this time. In the in vivo study, tumor burden in the mice was significantly reduced when nontoxic doses of TME (200 mg/kg b. wt and 400 mg/kg b. wt) were administered consecutively for 28 days. Considerable number of apoptotic cells was also observed in the biopsy analysis of tumor tissue of the TME-treated animals. The gas chromatographymass spectrometry analysis of the extract revealed 14 different compounds and the LC-MS analysis revealed ten secondary metabolites. Promising antitumor potential of T. involucrata by inducing apoptosis in lymphoma cells may be attributed to these molecules, and further, investigation is necessary to identify the active molecule and their mechanism of action, to obtain safer and effective anticancer drugs.