The increasing world population is driving demand for improved efficiency of feed resources of livestock. However, the molecular mechanisms behind various feed efficiency traits and their regulation by nutrition remain poorly understood. Here, we aimed to identify differentially expressed (DE) genes in the liver tissues of fattening Merino lambs and differences in metabolites accumulated in plasma to identify modified metabolic pathways as a consequence of milk restriction during the suckling period. Twenty-four male Merino lambs (4.81 ± 0.256 kg) were divided into 2 groups (n = 12 per dietary treatment). The first group (ad libitum, ADL) was kept permanently with the dams, whereas the other group (restricted, RES) was milk restricted. When they reached 15 kg of live body weight (LBW), all the animals were offered the same complete pelleted diet at the same level (35 g DM/kg LBW per day) to ensure no differences in dry matter intake. All the lambs were harvested when they reached 27 kg of LBW. For transcriptomic analysis, 4 liver samples from each group (8 samples in total) were selected for RNA sequencing (RNA-seq), and plasma samples from all animals (24 samples in total) were used to perform a nontargeted metabolomic analysis on a hybrid quadrupole-time-of-flight mass spectrometer coupled to an ultra-high performance liquid chromatographic system (UHPLC/QTOF-MS). Thirty-eight DE annotated genes were identified by RNA-seq, with 23 DE genes being down-regulated and 15 up-regulated in the liver of RES lambs relative to the ADL group (P < 0.10). Also, the metabolomic assay identified 38 differentially accumulated compounds (P < 0.10). In general, those genes and pathways involved in protein synthesis or protease inhibitors were down-regulated in the RES group, whereas those related to proteolytic degradation were up-regulated, thus suggesting a higher catabolism of proteins in these lambs. RES lambs showed over-expression of xenobiotic metabolism pathways, whereas those genes related to β-oxidation of fatty acids were down-regulated. According to the data obtained, early feed restriction during the suckling period of Merino lambs promoted long-term effects on both the hepatic transcriptomic profile and plasma metabolic profile, which might have modified fatty acids metabolism, catabolism of proteins, and detoxification of xenobiotics, thus reducing feed efficiency during the fattening period.