Increased body weight caused by visceral fat accumulation is on the rise and is reaching epidemic proportions worldwide. Hence, means and ways to tackle the problem of increased adiposity is of utmost importance. In this work, we report the effect of a water-soluble small molecule N,N-Dimethlyacetamide (DMA) on weight gain and adiposity in vitro and in vivo. To monitor the in vitro effect of DMA on adipogenesis, 3T3-L1 preadipocytes and pluripotent C2C12 cells were differentiated to adipocytes in the presence of DMA (5 mM and 10 mM). Oil red O staining and reverse transcriptase polymerase chain reaction (RT-PCR) were performed to evaluate the differentiation to adipocytes. To study the in vivo effect of DMA on body weight, experiments were done with C57BL/6J male mice (6 weeks old). The mice were randomly assigned to receive either high-fat diet (HFD; 45% fat) or a normal diet (7% fat) and were either intraperitoneally injected with DMA or phosphate-buffered saline (PBS) once a week for 20 weeks. Glucose tolerance test was performed on living mice. Post-experiment, the epididymal and subcutaneous adipose tissue were excised from the sacrificed animal, and histology, RT-PCR and plasma triglyceride assay were performed. DMA had no inhibitory effect on adipocyte differentiation when applied only once. However, sustained treatment with DMA inhibited the adipocyte differentiation in both 3T3-L1 and C2C12 cells, and significantly lowered the expression of adipocyte markers, in particular, fatty acid-binding protein 4 (fabp4). Under HFD, C57BL/6J mice treated with DMA had lower body weight compared with PBS treatment. Moreover, the HFD-induced higher body weight was controlled when the mice were switched from PBS to DMA treatment. Further, the HFD-mediated adipocyte hypertrophy from epididymal and subcutaneous adipose tissue was significantly reduced with DMA treatment. Interestingly, the glucose clearance and triglyceride levels in the plasma were improved in mice when DMA treatment was initiated early. Taken together, our results show that DMA exhibits a clear potential to prevent weight gain and restricts adiposity in response to high-fat feeding.