Hypoxia, or reduced oxygen, occurs in a variety of clinical and environmental situations. Hypoxic exposure is associated with decreased muscle mass and a concomitant reduction in exercise capacity, although the exact mechanisms are not completely understood. The activin receptor type IIB (ActRIIB) is a receptor for TGF superfamily members that are involved in the negative regulation of lean tissue mass. Given the negative effects of hypoxia on muscle mass and function and that modulation of ActRIIB has been shown to increase muscle mass, we tested the hypothesis that pharmacological targeting of ActRIIB for 2-weeks would attenuate the loss of muscle mass and function in mice following exposure to normobaric hypoxia. ActRIIB modulation was achieved using a soluble activin receptor/Fc fusion protein (sActRIIB) in mice housed in a hypoxic chamber for one- or two-weeks. Hypoxia induced a reduction in body weight in both PBS treated and sActRIIB treated mice, although treated mice remained larger throughout the hypoxic exposure. The absolute forces generated by extensor digitorum longus (EDL) muscles from sActRIIB treated mice were also significantly greater than PBS treated mice, and were more resistant to eccentric-contraction induced force drop following eccentric-lengthening contractions. In summary, sActRIIB pre-treatment attenuated hypoxia-induced muscle dysfunction in vitro. These data suggest that targeting the ActRIIB receptor is an effective strategy to counter hypoxia-induced muscle dysfunction and for pre-acclimatization to hypoxia in clinical or high altitude settings.