Background: In chronic kidney disease (CKD), the patients on a low-protein diet are considered to be at high risk of protein-energy wasting. Furthermore, a low-protein diet conceivably results in reduced intake of various nutrients. The purpose of this study was to evaluate the effects of a novel high-calorie, low-protein liquid formula containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), lactulose, raffinose, and indigestible dextrin on CKD patients. Methods: A randomized controlled trial was conducted on the Department of Nephrology at the Tokyo Medical University Hospital, Tokyo, Japan. Forty-three CKD patients prescribed a protein-restricted diet were randomly assigned to a supplement (SUP) or control (CTR) group. All patients received dietary counselling. Only the SUP group was given one or two packs (125 or 250 mL) daily of high-calorie, low-protein liquid formula. The intervention period was 16 weeks. Outcome measures of the study were body weight; body mass index (BMI); dietary protein, energy, and salt intake; estimated glomerular filtration rate (eGFR); serum levels of albumin, triglyceride and LDL-cholesterol; plasma fatty acid composition; plasma indoxyl sulfate level; creatinine clearance (Ccr); and urine protein excretion. Results: There were no differences in energy intake and protein intake between the two groups. Body weight, BMI, plasma eicosapentaenoic acid (EPA), and EPA/arachidonic acid (AA) ratio at 16 weeks were significantly higher in the SUP group than in the CTR group. At 16 weeks, the CTR group showed significant decline in eGFR and significant increase in plasma indoxyl sulfate, whereas the SUP group showed no significant changes from baseline. Conclusions: Supplementation of a novel liquid formula may be beneficial for the management in CKD patients on a protein-restricted diet.