Melanoma is a deadly form of malignancy and according to the World HealthOrganization 132,000 new cases of melanoma are diagnosed worldwide each year.Surgical resection and chemo/drug treatments opted for early and late stage ofmelanoma respectively, however detrimental post surgical and chemotherapyconsequences are inevitable. Noticeably melanoma drug treatments are associatedwith liver injuries such as hepatitis and cholestasis which are very common. Alleviationof these clinical manifestations with better treatment options would enhance prognosisstatus and patients survival. Natural products which induce cytotoxicity with minimumside effects are of interest to achieve high therapeutic efficiency. In this study weinvestigated anti-melanoma and hepatoprotective activities of frankincense essentialoil (FEO) in both in vitro and in vivo models. Pretreatment with FEO induce a significant(p < 0.05) dose-dependent reduction in the cell viability of mouse (B16-F10) andhuman melanoma (FM94) but not in the normal human epithelial melanocytes(HNEM). Immunoblot analysis showed that FEO induces down regulation of Bcl-2and up regulation of BAX in B16-F10 cells whereas in FM94 cells FEO induced dosedependent cleavage of caspase 3, caspase 9 and PARP. Furthermore, FEO (10 µg/ml)treatment down regulated MCL1 in a time-dependent manner in FM94 cells. In vivotoxicity analysis reveals that weekly single dose of FEO (1200 mg/kg body weight) didnot elicit detrimental effect on body weight during four weeks of experimental period.Histology of tissue sections also indicated that there were no observable histopathologic differences in the brain, heart, liver, and kidney compare to control groups. FEO (300and 600 mg/kg body weight) treatments significantly reduced the tumor burden inC57BL/6 mice melanoma model. Acetaminophen (750 mg/kg body weight) was used toinduce hepatic injury in Swiss albino mice. Pre treatment with FEO (250 and 500 mg/kgbody weight) for seven days retained hematology (complete blood count), biochemicalparameters (AST, ALT, ALK, total bilirubin, total protein, glucose, albumin/globulinratio, cholesterol and triglyceride), and the level of phase I and II drug metabolizingenzymes (cytochrome P450, cytochromeb5, glutathione-S-transferase) which wereobstructed by the administration of acetaminophen. Further liver histology showedthat FEO treatments reversed the damages (central vein dilation, hemorrhage, andnuclei condensation) caused by acetaminophen. In conclusion, FEO elicited markedanti-melanoma in both in vitro and in vivo with a significant heptoprotection.