Technical Abstract: Diet and nutritional status are critical factors that influences bone development. In this report, we demonstrate that a mixture of phenolic acids found in the serum of young rats fed blueberries (BB), significantly stimulated osteoblast differentiation, resulting in significantly increased bone mass. Greater bone formation in BB-fed animals was associated with increases in osteoblast progenitors and osteoblast differentiation, and reduced osteoclastogenesis. Blockade of p38 phosphorylation, eliminated effects of BB on activation of Wnt signaling in pre-osteoblasts. Knocking down beta-catenin expression also blocked the ability of serum from BB diet-fed rats to stimulate osteoblast differentiation in vitro. Based on our in vivo and in vitro data, we propose that the underlying mechanisms of these powerful bone promoting effects, occur through beta-catenin activation and the nuclear accumulation and transactivation, of TCF/LEF gene transcription in bone and in osteoblasts. These results, indicate stimulation of molecular events leading to osteoblast differentiation triggered by P38 MAPK/beta-catenin canonical Wnt signaling, results in significant increases in bone growth in young rats consuming BB-supplemented diets. LC/MS characterization of the serum after BB feeding revealed a mixture of simple phenolic acids, which may provide basis for developing a new treatment to increase peak bone mass and delay degenerative bone disorders such as osteoporosis.