Lightweight (LW) piglets from large litters display impaired growth performance compared with heavier littermates. This study investigated the growth performance and muscle development of early-weaned LW piglets (birthweight <1.2 kg) from large litters (17.3 ± 3.0 total born per litter), fed ad libitum a milk replacer supplemented with either l-carnitine (CAR) or l-arginine (ARG) from day 7 to day 28 of age. In total, 36 female and entire male Swiss Large White piglets, weaned on day 7 of age, were artificially reared in pairs in rescue decks. They were allocated to one of three dietary treatments: unsupplemented control (CON), 0.48 g l-carnitine per·piglet per·day (CAR) or 1.20 g l-arginine per kg body weight per·day (ARG). Milk replacer was prepared daily in a 1:4 powder-to-water ratio and fed ad libitum. Piglets were weighed at birth and on days 7, 14, 21 and 28. Feed intake was assessed daily. Piglets were euthanized on day 28. The entire semitendinosus muscle (STM) was collected, and organs were weighed. Subsequently, the STM was divided into the light (STMl) and dark (STMd) portion, and contractile and metabolic traits were analysed by ATP histochemistry, enzyme activities and gene expression. No differences in growth performance, organ and STM weight and on contractile traits were found between groups. A tendency (p < .10) for an elevated lipid oxidation enzyme activity in the STMl and STMd and greater (p < .05) phosphorylation of the mammalian target of rapamycin pathway in the STMl of CAR compared with CON piglets was found. Despite these metabolic responses, the lack of effect of CAR and ARG supplementation on growth performance suggests that providing the milk replacer ad libitum in combination with added CAR and ARG is insufficient for eliciting faster growth of LW piglets.