During obesity treatment, clinicians have been burdened by the ever-increasing number of patients and the side effects of drug treatment. Finding new plant-derived active ingredients as an intervention for obesity has become a research focus. In this study, Plackett-Burman and Central Composite Design experiments, plant-wide target metabolomics technology, simulated human colon fermentation test, and cell experiment in vitro were successively used to investigate the effects of fermented and unfermented polyphenols (FP and UP, respectively) of blue honeysuckle on obesity. After the optimization of the response surface method, polyphenol content ((1 878.08 ± 14.53) mg/100 g) increased by 2.63 times after Lactobacillus rhamnosus 6224 and Saccharomyces cerevisiae W5 mixed fermentation. There were 23 significantly different metabolites were observed in FP and UP. Of them, 7 different metabolites were significantly and positively correlated with short-chain fatty acids (SCFAs), whereas negatively correlated with lipopolysaccharides (LPS). The contents of these 7 metabolites were significantly increased in FP. Furthermore, the effects of FP and UP on the SCFA biosynthesis pathway were different. Cell experiments revealed that polyphenols can significantly promote the secretion of gastrointestinal endogenous hormones and insulin and inhibit interleukin-6 levels. Linear regression analysis revealed SCFAs had a positive regulatory effect on glycolipid metabolism, whereas LPS had a negative effect. Overall, these crucial findings provide an economical and simple method for obtaining blue honeysuckle polyphenols and laying a theoretical foundation for its application in the therapeutic intervention against obesity.