Obesity has become a worldwide burden and is associated with severe medical complications. Geraniin is a polyphenolic compound that has a wide range of bioactive properties. There is also evidence to support its pharmacological effects on improving lipid accumulation and obesity. This research investigates the effect of geraniin on lipid accumulation in adipocytes and the underlying mechanism. Mature adipocytes were differentiated from immature 3T3-L1 cells. Oil Red O staining and a triglyceride content determination were conducted to evaluate the intracellular lipid accumulation. Molecular docking studies were performed to determine the interaction between geraniin and the key proteins. Western blotting was used to detect the expression of lipogenic enzymes and transcription factors. Geraniin dose-dependently inhibited lipid accumulation in adipocytes by reducing the expression of fatty acid synthase and increasing the phosphorylation level of acetyl-coenzyme A carboxylase. Moreover, geraniin promoted the phosphorylation of AMP-activated protein kinase (AMPK) and further reduced the expression of lipogenic transcription factors (peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha). The expression of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) was increased by the geraniin administration. The molecular docking study demonstrated that geraniin can interact with CaMKK2, which is an upstream kinase of AMPK. A selective CaMKK2 inhibitor reversed the suppressive effect of geraniin on lipogenesis. Geraniin targeted CaMKK2 to inhibit lipid accumulation in 3T3-L1 adipocytes by suppressing lipogenesis, and this supports its potential as a candidate natural anti-obesity drug.