Plants and herbivores have been in an evolutionary arms race for millions of years; however, ongoing climate change is modifying the global distributions of plant and animal species at an accelerated pace, exposing herbivores to plants with novel chemical defenses. Little is known about the physiological mechanisms that enable mammalian herbivores to feed on toxic plants, although the liver is thought to play a key role. To improve our understanding of the liver's role in facilitating toxin tolerance, we investigated the mechanisms that enable the desert woodrat (Neotoma lepida) to feed on the highly toxic creosote bush (Larrea tridentata), a desert shrub that rapidly expanded across the Southwestern United States at the end of the Pleistocene. We brought woodrats into captivity, fed them experimental diets containing creosote bush, sequenced total liver RNA, and isolated protein from liver tissue. Using this approach, we identified a high diversity of detoxification enzymes that were induced in response to creosote bush feeding, including several cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UGTs), and ATP-binding cassette transporters (ABCs). We used chemiluminescence western blotting to confirm the presence of several of these highly-expressed enzymes. Our results further implicate the role of the liver in facilitating toxin tolerance, improve our understanding of what substrates induce the expression of endogenous liver enzymes, and broaden our knowledge of how mammalian herbivores may adapt to environmental change.