The common brushtail possum (Trichosurus vulpecula) and the short-eared possum (T. caninus) are closely related but differ in several aspects of their life-history strategy, habitat and diet preferences. Both are generalist herbivores, but T. vulpecula consumes significant amounts of Eucalyptus spp. foliage, while T. caninus instead feeds mainly on Acacia spp. Eucalypt foliage is protected against herbivory by several classes of plant secondary compounds, including terpenes and tannins, while acacia foliage is protected mainly by tannins. We compared the responses of these two possum species to the addition of either sesquiterpenes or a hydrolysable tannin to a basal diet free of these compounds. In both species, sesquiterpenes tended to reduce food intake, and increased plasma concentrations of albumin and decreased concentrations of bicarbonate, the latter consistent with changes in acid–base balance. Tannic acid significantly depressed food intake in both species, and depressed plasma concentrations of total protein, albumin, glucose, sodium and chloride, consistent with dehydration. T. vulpecula increased urinary glucuronic acid excretion three-fold in response to dietary sesquiterpenes but there was no increase in T. caninus. T. vulpecula had five- to six-fold greater plasma concentrations of bilirubin, a potent antioxidant, than did T. caninus across all treatments. Results suggest that T. vulpecula can better withstand the detrimental effects of plant secondary compounds, consistent with its wider spectrum of foods and broader habitat preferences.