Objective To explore the impact of early nutrition combined with early mobilization based on the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines on ICU-acquired weakness (ICU-AW). MethodsA total of 120 ICU patients treated at our hospital from March 2022 to May 2024 were randomly divided into a test group (n=60) and a control group (n=60). All patients received routine supportive care. In addition, the test group received early nutrition based on ESPEN guidelines combined with early mobilization intervention, while the control group received only early mobilization. Baseline data were collected at admission, and ICU length of stay, duration of mechanical ventilation, mortality, and Δ Sequential Organ Failure Assessment (SOFA) scores were recorded at discharge. Differences in the British Medical Research Council (MRC) score, Barthel Index (BI), and Subjective Global Assessment (SGA) rating were compared between admission and discharge for both groups. Results At discharge, the test group showed significantly lower rates of ICU-AW and shorter ICU stays compared to the control group (All P<0.05). The MRC score was significantly higher, and the SGA rating was lower in the test group compared to the control group (All P<0.05). Logistic regression analysis showed that high APACHE Ⅱ scores and SGA grade C were independent risk factors for ICU-AW, while high MRC scores and the addition of early nutrition based on ESPEN guidelines were protective factors (All P<0.05). Conclusion Compared to early mobilization alone, the addition of early nutrition based on ESPEN guidelines may be more effective in improving nutritional status and muscle condition, thereby reducing the occurrence of ICU-AW and enhancing functional independence