AIM: A growing interest to understand the signaling pathways mediating obesity-induced muscle atrophy is given. Metformin (Met) was reported to possess positive effects on preventing muscle damage and promoting muscle mass maintenance. The aim of the present study to investigate pathways involved in Met effect on obesity induced muscle atrophy. METHODS: Thirty adult male albino rats were assigned into two groups: normal chew diet fed group as control group (C; n = 10) and high-fat-diet (HFD) fed group ( n = 20). After 16 weeks, the HFD-fed animals were subdivided into two groups; HFD group ( n = 10) and HFD fed treated with oral Met (320 mg/day) treatment (Met, n = 10) for 4 weeks. At the end of the experiment; final body weight, visceral fat weight, fasting blood glucose, insulin, lactate, total cholesterol, triglycerides were measured and calculated homeostatic model assessment insulin resistant (HOMA-IR) for all groups. Soleus muscle weight, histopathlogical examination and expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), forkhead box O3 (FoxO3), atrogin-1/MAFbx, and muscle RING finger 1 (MuRF-1) were performed. RESULTS: HFD-fed animals showed significant increase in final body weight, visceral fat mass, fasting blood glucose, insulin, calculated HOMA-IR, lactate, total cholesterol and triglycerides with significant decrease in soleus muscle weight, PGC-1α and significant increase in FoxO3, atrogin-1/MAFbx, and MuRF-1 expression. Also, there was significant decrease in fiber diameter, myosin heavy chain (MHC) I content while collagen content and myosin heavy chain IIa were increased compared with control group. Met-treated group showed a significant decrease in the measured parameters compared with the HFD group. It also restored the gene expression, morphometric measures and MHC composition toward normal. CONCLUSION: The current study is the first to provide evidence that Met could ameliorate muscle atrophy in high-fat diet induced obesity and this effect may be in part due to regulation of PGC-1α-FoxO3 pathway.