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Chenopodium ambrosioides have been used for centuries in the Americas as a popular remedy for parasitic diseases. The essential oil of this plant possesses anthelmintic activity and is still used in some regions to treat parasitosis and leishmaniasis. However, the Chenopodium oil caused also some fatalities, leading to its commercial disuse. In this work, we studied the mechanism of toxicity of the essential oil and its major pure ingredients (carvacrol, caryophyllene oxide, and ascaridole, which was synthesized from α-terpinene) with respect to mammalian cells and mitochondria. We observed that all products, but especially caryophyllene oxide, inhibited the mitochondrial electron transport chain. This effect for carvacrol and caryophyllene oxide was mediated via direct complex I inhibition. Without Fe2+, ascaridole was less toxic to mammalian mitochondria than other major ingredients. However, evidence on the formation of carbon-centered radicals in the presence of Fe2+ was obtained by ESR spin-trapping. Furthermore, it was shown that Fe2+ potentiated the toxicity of ascaridole on oxidative phosphorylation of rat liver mitochondria. The increase of the α-tocopherol quinone/α-tocopherol ratio under these conditions indicated the initiation of lipid peroxidation by Fe2+-mediated ascaridole cleavage. Further ESR spin-trapping experiments demonstrated that in addition to Fe2+, reduced hemin, but not mitochondrial cytochrome c can activate ascaridole, explaining why ascaridole in peritoneal macrophages from BALB/c mice exhibited a higher toxicity than in isolated mitochondria.