Insufficient and delayed fracture healing remain significant public health problems with limited therapeutic options. Phosphoinositide 3-kinase (PI3K) signaling, a major pathway involved in regulation of fracture healing, promotes proliferation, migration, and differentiation of osteoprogenitors. We have recently reported that knock-in mice with a global increase in PI3K signaling (gCblYF) show enhanced femoral fracture healing characterized by an extraordinary periosteal response to injury. Interestingly, of all growth factor receptors involved in fracture healing, PI3K directly binds only to PDGFR. Given these findings, we hypothesized a PDGFR-PI3K interaction is necessary for mediating robust periosteal cell activation following fracture. In this study, we isolated primary periosteal cells from gCblYF mice to analyze cross-talk between the PDGFRβ and PI3K signaling pathways. We found PDGFRβ signaling contributes to robust Akt phosphorylation in periosteal cells in comparison with other growth factor signaling pathways. Additionally, we performed femoral fractures on gCblYF mice with a conditional removal of PDGFRβ in mesenchymal progenitors using inducible alpha smooth muscle actin (αSMA) CreERT2 mice. Our studies showed that depletion of PDGFRβ signaling within these progenitors in the early phase of fracture healing significantly abrogates PI3K-mediated periosteal activation and proliferation three days after fracture. Combined, these results suggest that PDGFRβ signaling through PI3K is necessary for robust periosteal activation in the earliest phases of fracture healing.