Background: Fatigue, a common problem in modern society, reduces quality of life and productivity, highlighting the need for natural remedies. Curcuma xanthorrhiza Roxb., a well-known Indonesian plant medicine, is recognized for its diverse bioactivities, mainly attributed to its marker compound xanthorrhizol (XTZ). Aim: This study investigated the antifatigue activity of C. xanthorrhiza extracts extracted by an eco-friendly natural deep eutectic solvent (NADES), composed of choline chloride and sucrose (CC-Suc 3:1, 10% water). Methods: Male Balb/c mice were randomly divided into seven groups (n = 4). Each group was orally administered for 28 days vehicles (carboxymethyl cellulose and CCSuc), the positive control (taurine 700 mg/kg/BW), C. xanthorrhiza extracted by CC-Suc or ethanol equivalent to 10 or 25 mg XTZ/kg BW. The effect of treatment on exercise performance was evaluated by forced swimming test (FST) and changes in fatigue-related parameters. Results: C. xanthorrhiza extracts prolonged FST time in a dose-dependent manner, increased muscle ATP and adenosine 5-monophosphate-(AMP-) activated protein kinase (AMPK) levels. Treatment with ethanol extracts of C. xanthorrhiza reduced serum urea nitrogen in a dose dependent trend compared with the vehicle group. No significant differences were observed in hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating absence of liver toxicity. Conclusions: These findings demonstrate that NADESbased C. xanthorrhiza extract improves exercise endurance, possibly through modulation of energy metabolism. Moreover, the choline chloride–sucrose NADES serves as a safe and sustainable extraction solvent and delivery medium, supporting potential use of C. xanthorrhiza as a functional food ingredient against fatigue. © 2026, Walailak University. All rights reserved.