The cytotoxicity of Helichrysum odoratissimum against human epidermoid carcinoma (A431), malignant melanoma (A375), cervical epithelial carcinoma (HeLa) and human embryonic kidney (HEK-293) cells was investigated. The cytokine production and antioxidant activity was also determined. H odoratissimum was selected based on its traditional usage as a dressing for wounds. In this study the cytotoxicity was performed on skin and cervical cancer which are associated with the presence of wounds. H. odoratissimum showed inhibitory activity against A431 cells, with a fifty percent inhibitory concentration (IC50) of 15.5±0.2 μg/ml, and a high DPPH inhibition with an IC50 of 5.13±0.07 μg/ml. A431 cells treated with the extract showed an increase in morphological characteristics associated with apoptosis. The extract induced IL-12 in U937 cells and inhibited IL-8 at the tested concentrations, with the highest levels being 12.4±7 pg/ml and 103±6.1 pg/ml respectively. IL-2 was inhibited by 56 % and 52 % in naive and PHA induced murine splenocytes respectively. Furthermore, 2 lipophilic fractions and 3 compounds were isolated from the extract. The lipophilic fractions showed relative cytotoxicity on A431 cells with IC50 values of 175±13.5 μg/ml and 61.3±0.16 μg/ml. The extract showed significant hepatoprotection at 25 μg/ml on HepG2 cells exposed to D-Galactosamine. This is the first report of the activity of H. odoratissimum ethanolic leaf stem extract on A431, A375, HeLa and HEK-293 cell lines as well as the isolation of two promising lipophilic fractions.