Fermentation is a technique commonly used to improve the health of agricultural products. In this study, Dendrobium officinale leaves were solid-state fermented by edible fungi, and the results showed that Aspergillus oryzae was the suitable strain to increase their inhibition abilities against α-glucosidase and α-amylase by 9.05- and 2.99-times, respectively. Chemical analysis showed that the contents of total phenolics, free phenolics, bound phenolics, quercetin and rhoifolin were increased by 2.54-, 3.41-, 2.09-, 6.03-, and 8.06-times, while those of luteolin, gallic acid, and kaempferol were increased from undetectable level to 0.45, 46.99, and 4.47 μg/g, respectively, after four days of fermentation by A. oryzae. Furthermore, the hypoglycemic activity of D. officinale leaves was tested in vivo. The fermented group showed higher capacity for decreasing fasting blood glucose levels and insulin resistance, reversing dyslipidemia, ameliorating oxidative stress, and reversing pancreatic and liver lesions in db/db mice. These findings suggest that it is effective to utilize and valorize D. officinale leaves as functional food or food additives through the fermentation by A. oryzae.