Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed either ad libitum (AL) or a 30% CR diet from 9-13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both on fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency in the context of ad libitum diet (AL) or obesity, and occurred without changes in insulin secretion or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance under CR. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilisation that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. Together, our findings suggest that adiponectin tunes glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. The widely reported functions of adiponectin in pathological states, including obesity and insulin resistance, thus differ sharply from its roles during CR, with marked sexual dimorphism apparent for many of these functions.