Zebrafish tissues and organs display exceptionally robust self-repair capabilities. For example, damaged fins are readily restored, which entails perfectly regenerating bony ray structures, each comprising two semi-cylindrical bones that encase mesenchymal cells, nerves, and blood vessels. Bone regeneration in fin rays is mediated by injury-induced progenitor osteoblasts (pObs) that later redifferentiate to produce replacement bone. Two opposing signaling pathways, Wnt/β-catenin and BMP, balance competing demands for pOb renewal and differentiation, respectively, until regeneration is complete. To identify additional factors that directly influence Obs, we performed an in vitro screen using a pOb-like cell line derived from regenerating fins. Unexpectedly, we found that insulin or insulin-like growth factor (IGF), combined with dexamethasone, is sufficient to stimulate Ob differentiation. mTOR signaling is required for insulin/IGF-driven differentiation both in vitro and in regenerating fins. Using a novel O-propargyl-puromycin and click chemistry-based approach, we determined that re-differentiating fin Obs dramatically and specifically upregulate mTOR-dependent protein anabolism. We suggest that during an initial “burst” phase of bone regeneration, locally produced IGF2b stimulates full Ob differentiation. Concomitant with re-vascularization, regenerating bone then enters a “steady-state” phase, when the restored blood supply delivers circulating insulin to sustain Ob maturation. At both phases, we propose bone maturation integrates Ob-autonomous BMP signaling, which maintains a specific differentiated Ob transcriptional program, with insulin/IGF environmental cues that promote sufficient mTOR-dependent protein synthesis to generate a robust bone matrix.