Polypeptides synthesized from α-amino acid N-carboxyanhydrides are considered ideal candidates as scaffold materials for bone tissue engineering due to their excellent biocompatibility and non-toxic degradation products. However, undesirable mechanical properties and osteoinductivity restrict their application in bone healing and regeneration. To overcome these limitations, we modified a synthetic polypeptide poly(N_ε-Cbz-L-lysine) (PZL) with poly(lactic-co-glycolic acid) (PLGA) having relatively high strength and osteoinductive bioglass (BG) particles, and fabricated foamy PZL/PLGA/BG composite scaffolds using a negative NaCl-templating method. The morphology, compression modulus, thermal and degradation behaviors of the PZL/PLGA/BG composite scaffolds were characterized, and the in vitro biocompatibility was evaluated with MC3T3-E1 cells using live/dead staining, MTT and ALP assays. The results indicated that the PZL/PLGA/BG composite scaffold with a weight ratio of 5 : 5 : 1 (PZL5PLGA5BG) had higher compression modulus and protein adsorption and mineralization abilities than other scaffolds, and was more conducive to the adhesion, proliferation and osteoblastic differentiation of MC3T3-E1 cells. The in vivo biocompatibility of the scaffolds was evaluated in both rat subcutaneous model and rabbit tibia defect model. The results of histological studies of subcutaneous implants, as confirmed by H&E, Masson's trichrome and CD34 staining assays, demonstrated that the PZL5PLGA5BG composite scaffolds allowed the ingrowth of tissue and microvessels and exhibited reduced inflammation response as compared to other scaffolds after 8 weeks of implantation. In experimental studies in bone defect model, the results of digital radiography and H&E staining confirmed that the PZL5PLGA5BG composite scaffolds after 8 weeks of implantation significantly improved in vivo osteogenesis. The newly formed bone tissue grew into the scaffolds along with the degradation of the materials. To sum up, the foamy PZL/PLGA/BG composite scaffolds had good comprehensive performances and would meet the needs of bone regeneration.