The aim of this study was to investigate the effects of resveratrol (RSV) on cigarette smoke (CS)-induced skeletal muscle atrophy and senescence in mice with emphysema and to explore the underlying mechanisms. Gastrocnemius muscle weight and lung and muscular morphology were observed in CS-exposed mice with or without RSV treatment. The expression of atrophy-related markers (MURF1 and MAFbx), senescence-related markers (P53, P21 and SMP30) and NF-κB inflammatory pathways was detected by Western blotting and real-time PCR. The levels of IL-1β and TNF-α were also determined by ELISA, and the number of senescent cells was determined by SA-β gal staining. In addition, the expression of HDAC2 and the effect of HDAC2 on CSE-induced skeletal muscle atrophy and senescence by RSV treatment were investigated. RSV prevented emphysema and skeletal muscle atrophy in long-term CS-exposed mice. RSV decreased the expression of MURF1, MAFbx, P53, and P21 and inhibited the NF-κB pathway both in vivo and in vitro. Moreover, RSV reversed CS-induced downregulation of HDAC2 expression both in gastrocnemius and in C2C12 cells. Moreover, knockdown of HDAC2 significantly abolished the inhibitory effect of RSV on the expression of MURF1, MAFbx, P53, P21 and inflammatory factors (IL-1β and TNF-α) in C2C12 cells. RSV prevents CS-induced skeletal muscle atrophy and senescence, and upregulation of HDAC2 expression and suppression of inflammation are involved.