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Background: The in vivo anticancer effect of the Trema orientalis leaves crude methanol extract (TLME) was screened against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Materials and methods: The cytotoxic activity of TLME was determined in vitro by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The growth inhibitory activity and morphological alterations were determined by the hemocytometer counting of the EAC cells using trypan blue dye. The apoptotic cells were assessed by DAPI (4′,6-diamidino-2-phenylindole) staining. The hematological and biochemical parameters of experimental mice were also estimated. Results: After treatment with the TLME, the viable tumor cell count, morphological changes and nuclear damages of the EAC cells were observed along with the hematological parameters of the experimental mice. The LD50 of TLME was 3120.650 mg/kg body weight, and this extract was proven to be safe at a dose of as high as 800 mg/kg body weight. The oral administration of the TLME at 400 mg/kg body weight resulted in approximately 59% tumor cell growth inhibition compared with the control mice, with considerable apoptotic features, including membrane blebbing, chromatin condensation, nuclear fragmentation and aggregation of the apoptotic bodies in DAPI staining under a fluorescence microscope. The TLME also dose-dependently restored the altered hematological parameters to approximately normal levels. The TLME exhibited bolstering cytotoxic effect against the EAC cell with the IC50 value of 29.952 ± 1.816 μg/mL. Conclusion: The TLME has potential as a natural anti-cancer product with apoptosis induction property and cytotoxicity against carcinoma cells. [ABSTRACT FROM AUTHOR]