BACKGROUND As an enzymatic product of yeast, yeast‐based nucleotide (YN) is rich in nucleotides. To test the effects of maternal dietary supplementation with YN during late pregnancy on placental nutrient transport and nutrient metabolism in neonatal piglets, 64 pregnant sows (day 85 ± 3) were assigned into two groups: (i) control (CON) and (ii) treatment (YN; 4 g kg−1). Blood, placenta and liver samples of neonates during delivery were collected. RESULTS The results showed that maternal YN supplementation decreased stillbirth rate and intra‐uterine growth restriction rate (P < 0.05). In addition, maternal YN supplementation increased total serum protein, albumin and total cholesterol (P < 0.05). Furthermore, in neonatal piglets in the YN group, both serum amino acidand nucleotide profiles were affected, as well as liver amino acid, and fatty acid profiles were regulated (P < 0.05). Moreover, maternal YN supplementation increased liver mRNA expression of SLC28A3, SLC29A1, SLC29A2, PC, PCK1, FBP1, SREBP1c, HSL and CYP7a1 of neonatal piglets (P < 0.05). Meanwhile, there was a decrease in placental gene expression of EAAT2, EAAT3, LAT1 and PAT1, as well as lower protein expression of peroxisome proliferator‐activated receptor (PPAR)γ, AKT, phosphorylated‐AKT, phosphorylated‐mammalian target of rapamycin (mTOR) and Raptor, in the YN group (P < 0.05). CONCLUSION Taken together, these results indicate that maternal YN supplementation regulates placental nutrient transport by regulating the mTOR complex 1‐PPAR pathway, and affects the liver metabolism of nucleotides, amino acids and fatty acids in neonatal piglets, thereby improving the reproductive performance of sow to a certain extent. © 2020 Society of Chemical Industry