Background: Liver physiology is sensitive to estrogens, which suggests that the liver might be a target of estrogenic endocrine disrupters (EED). However, the long-term consequences of neonatal exposure to EED on liver physiology have rarely been studied. The nuclear receptor small heterodimer partner (SHP) mediates the deleterious effects of neonatal exposure to diethylstilbestrol (DES) on male fertility. Objectives: As SHP is involved in liver homeostasis, we aimed to determine whether neonatal estrogenic exposure also affected adult liver physiology through SHP. Male mouse pups were exposed to DES in the first 5 days of life. Results: DES exposure leads to alterations in the postnatal bile acid (BA) synthesis pathway. Neonatal DES-exposure affected adult liver BA metabolism and subsequently triglyceride (TG) homeostasis. The wild-type males neonatally exposed to DES exhibited increased liver weight and altered liver histology in the adult age. The use of deficient male mice revealed that SHP mediates the deleterious effects of DES treatment. These long-term effects of DES were associated with differently timed alterations in the expression of epigenetic factors. Conclusions: However, the molecular mechanisms by which neonatal exposure persist to affect the adult liver physiology remain to be defined. In conclusion, we demonstrate that neonatal DES exposure alters adult hepatic physiology in an SHP-dependent manner.