Sarcopenia is the progressive loss of skeletal muscle mass and function with advancing age, leading to reduced mobility and quality of life. We tested the hypothesis that antibody‐directed myostatin inhibition would attenuate the decline in mass and function of muscles of aged mice and that apoptosis would be reduced. Eighteen‐month‐old C57BL/6 mice were treated for 14 wk with a once‐weekly injection of saline (control, n=9) or a mouse chimera of anti‐human myostatin antibody (PF‐354, 10 mg/kg; n=12). PF‐354 prevented the age‐related reduction in body mass and increased soleus, gastrocnemius, and quadriceps muscle mass (P<0.05). PF‐354 increased fiber cross‐sectional area by 12% and enhanced maximum in situ force of tibialis anterior (TA) muscles by 35% (P<0.05). PF‐354 increased the proportion of type IIa fibers by 114% (P<0.01) and enhanced activity of oxidative enzymes (SDH) by 39% (P<0.01). PF‐354 reduced markers of apoptosis in TA muscle cross‐sections by 56% (P<0.03) and reduced caspase3 mRNA by 65% (P<0.04). Antibody‐directed myostatin inhibition attenuated the decline in mass and function of muscles of aging mice, in part, by reducing apoptosis. These observations identify novel roles for myostatin in regulation of muscle mass and highlight the therapeutic potential of antibody‐directed myostatin inhibition for sarcopenia.—Murphy, K. T., Koopman, R., Naim, T., Léger, B., Trieu, J., Ibebunjo, C. Lynch, G. S. Antibody‐directed myostatin inhibition in 21‐mo‐old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function. FASEB J. 24, 4433–4442 (2010). www.fasebj.org