Objective:To observe the effects of Da Chaihutang on Cyclic adenosine monophosphate （cAMP）-response element binding protein （CREB）/peroxisome proliferator-activated receptor-gamma coactivator-1 alpha （PGC-1α） pathway in nutritionally obese rats and the protective mechanism on liver mitochondria. Method:A total of 120 8-week-old male SD rats were randomly divided into a control group （n=20） and an experimental group （n=100）. The rats in the control group were fed on a normal diet， while those in the experimental group were administered with a high-fat feed. Successfully modeled rats were randomly divided into a model group， a positive drug （metformin） group， and low-， medium- and high-dose Da Chaihutang groups （4.25， 8.5， and 17 g∙kg^-1， respectively）， with 20 rats in each group. After treatment with Da Chaihutang， the body weight， Lee's index， liver mitochondrial membrane potential and mitochondrial ultrastructure， PGC-1α expression and CREB phosphorylation of each group were measured and compared. Result:Compared with the control group， the model group showed increased body weight and Lee's index （P<0.01）， whereas decreased mitochondrial membrane potential， PGC-1α expression， and CREB phosphorylation level （P<0.01）. As compared with the model group， Da Chaihutang significantly reduced the body weight and Lee's index of obese rats （P<0.05， P<0.01）， enhanced liver mitochondrial membrane potential （P<0.05， P<0.01） to protect the integrity of mitochondrial structure， up-regulated PGC-1α expression and promoted CREB phosphorylation （P<0.05， P<0.01）. Conclusion:Da Chaihutang protects the structure and function of mitochondria and inhibits weight gain in obese rats by activating the CREB/PGC-1α pathway.