Medicinal plant is considered  a double edged sword that could be beneficial or toxic to people or animals. Accordingly, this study is concerned with vitro and vivo evaluation ofEuphorbiaschimperiana and Euphorbia balsamiferatoxicity in rats. A comparison study was carried out between both extracts on THLE2 and WI38 cell lines. Furthermore, the anti-inflammatory and the anti-mutagenicity influence of both target plants were studied in rats administrated monoiodoacetate. The study was supported by biochemical and the histological examinations of key organs. Methanol extract of  E.schimperiana and E. Balsamifera displayed IC₅₀ values of 30.6±1.96 and 88.7±5.67 respectively on WI38 cell lines. The chloroform fraction of E. schimperiana showed the greatest safety profile  with IC₅₀ value of 72±3.74 while  petroleum ether fraction of  E. balsamifera displayed the maximum safety profile among the other fractions with IC₅₀ value of 56 ±3.74 onTHLE2  cells. Male Wistar rats administered orally 2.5 mg/kg of methanol extract did not show any fatalities or ill effects. The daily dose of the two extracts demonstrated a substantial dose dependent decrease in the percentage of MNPEs and chromosomal abnormalities; due to mono-iodoacetate administration, suggesting the valuable role of  the target plants.