Background: The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferator-activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents. Objectives: In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action. Methods: As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses. Results: DEHP-treated mice were protected from diet-induced obesity via PPARα-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARβ nor PPARγ was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARα-humanized mice. These species differences are associated with a different pattern of coregulator recruitment. Conclusion: These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARα signaling and highlight the metabolic importance of the species-specific activation of PPARα by xenobiotic compounds.