Background and aims Muscle wasting is frequently observed in critically ill patients, leading to increased rates of complications and mortality, and could be determined by measuring the quadriceps femoris muscle thickness (QFMT). One significant contributing factor is inflammation, with interleukin-6 (IL-6) as one of the important markers. Branched-chain amino acids (BCAAs), especially leucine, enhance muscle protein synthesis, and reduce inflammation. This study examined the effects of high leucine BCAA supplementation on QFMT and IL-6 levels in critically ill patients. Methods This multicentre, double-blind, randomised controlled trial was conducted in two hospitals in Indonesia from December 2023 to May 2024. Recently admitted critically ill patients were randomly assigned to receive 40 g/day of BCAA (19 g/day of leucine, with a ratio of leucine : isoleucine : valine = 2:1:1.2) supplementation, either enterally or partial parenterally, for 10 days, or to a control group. QFMT was measured using an ultrasound (US), and IL-6 serum levels were measured at baseline and day 10. We performed a linear mixed model to analyse the effects of other factors on outcomes. Results Forty participants were included in this study; most (78 %) were male, median age 49 (21), and had a surgical diagnosis (55 %). Patients in both groups had similar initial QFMT and IL-6 levels. On day 10 of the study, loss of muscle thickness was found to be less prominent in the BCAA than the control group (0 vs. −13 %, p = 0.001), and the BCAA group showed a significant reduction in IL-6 levels than control (−59.1 vs. 126.5 pg/mL, p = 0.012). Conclusion Supplementing critically ill patients with high leucine BCAA potentially attenuates muscle mass loss and reduces IL-6 levels. Registration number NCT06167772. © 2025 The Author(s).