Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half-life of active (acylated) ghrelin (~11min in humans). EXT418 is a novel long-acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)-induced cachexia in mice. Male C57BL/6J mice (5- to 7-month-old) were implanted with 1×106 heat-killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T+V) or EXT418 daily (T+418 Daily, 0.25mg/kg/day) or every other day (T+418 EOD, 0.5mg/kg/EOD) for up to 14days, whereas HK-treated mice were given vehicle (HK+V). Subsets of T+418 Daily or EOD-treated mice were pair-fed to the T+V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination. In tumour-bearing mice, administration of EXT418 daily or EOD partially prevented weight loss (T+V vs. T+418 Daily, P=0.030; and vs. T+418 EOD, P=0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour-bearing mice was improved by EXT418 daily (P=0.010) or EOD (P=0.008) administration compared with vehicle-treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418 daily administration also improved type IIA (P=0.015), IIB (P=0.037) and IIX (P=0.050) fibre cross-sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P=0.005). In skeletal muscles, tumour-induced increases in atrogenes Fbxo32 and Trim63 were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3 (GAS/PL; P≤0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P=0.039). In addition, EXT418 treatments ameliorated the tumour-induced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Il-6 transcript levels in adipose tissue and circulating IL-10 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418. EXT418 mitigates LLC-induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.