The goal of this project was to determine the effects of domperidone given throughout lactation on hormonal and metabolic status, lactational performance, and gene expression in mammary epithelial cells of sows. Second parity sows were divided in two treatment groups: 1) daily intramuscular injections with canola oil (Control, CTL, n = 24), or 2) daily intramuscular injections with 0.5 mg/kg body weight (BW) of domperidone (DOMP, n = 23). Injections were given at 08h05 starting the day after farrowing until weaning. Over the first 4 d of treatment, DOMP sows also received 0.5 mg/kg BW of domperidone per os twice daily, whereas CTL sows were fed the vehicle. Litter size was standardized to 11 ± 1 within 24 h of birth and piglets were weighed at birth, 24 h postpartum, and on days 7, 22 (weaning on day 23), 35, and 56. Sow feed intake was recorded daily. Representative milk samples were obtained aseptically on day 21 of lactation from 15 sows per treatment for compositional analyses and milk fat globules were used to measure mRNA abundances of various genes. Jugular blood samples were obtained from all sows on days 2, 8, 16, and 23 of lactation to measure concentrations of prolactin, insulin-like growth factor-1 (IGF-1), leptin, adiponectin, insulin, glucose, urea, and free fatty acids (FFA). Concentrations of prolactin (P < 0.001) and FFA (P < 0.01) were increased in DOMP compared with CTL sows, whereas concentrations of insulin were decreased (P < 0.05). Urea concentrations were increased by treatment (P < 0.05) on days 16 and 23 of lactation, and those of IGF-1 were increased (P < 0.01) on day 16. Piglets from DOMP sows were heavier than those from CTL sows on day 22 (P < 0.01). Milk composition was unaffected by treatment. The mRNA abundance in milk fat globules for casein beta and whey acidic protein were lower (P ≤ 0.05) in DOMP than CTL sows. The long form of the prolactin receptor and the signal transducer and activator of transcription 5A mRNA abundances tended to be lower (P < 0.10) in DOMP than CTL sows. In conclusion, hyperprolactinemia induced by domperidone during lactation affected the endocrine and metabolite status of sows and stimulated growth of their suckling piglets.