Restrictive feeding influences systemic metabolism of nutrients; however, this impact has not been evaluated in chickens of diverging feed efficiency. This study investigated the effect of ad libitum versus restrictive feeding (85% of ad libitum) on the serum metabolome and white blood cell composition in chickens of diverging residual feed intake (RFI; metric for feed efficiency). Blood samples were collected between days 33 and 37 post-hatch. While serum glucose was similar, serum uric acid and cholesterol were indicative of the nutritional status and chicken's RFI, respectively. Feed restriction and RFI rank caused distinct serum metabolome profiles, whereby restrictive feeding also increased the blood lymphocyte proportion. Most importantly, 10 amino acids were associated with RFI rank in birds, whereas restrictive feeding affected almost all detected lysophosphatidylcholines, with 3 being higher and 6 being lower in restrictively compared to ad libitum fed chickens. As indicated by relevance networking, isoleucine, lysine, valine, histidine, and ornithine were the most discriminant for high RFI, whereas 3 biogenic amines (carnosine, putrescine, and spermidine) and 3 diacyl-glycerophospholipids (38:4, 38:5, and 40:5) positively correlated with feed intake and body weight gain, respectively. Only for taurine, feed intake mostly explained the RFI-associated variation, whereas for most metabolites, other host physiological factors played a greater role for the RFI-associated differences, and was potentially related to insulin-signaling, phospholipase A2, and arachidonic acid metabolism. Alterations in the hepatic synthesis of long-chain fatty acids and the need for precursors for gluconeogenesis due to varying energy demand may explain the marked differences in serum metabolite profiles in ad libitum and restrictively fed birds.