The aim of current study was to evaluate the effect of nano-apatitic particles (nAp) incorporation on the degradation characteristics and biocompatibility of poly(lactide-co-glycolide) (PLGA)-based nanofibrous scaffolds. Composite PLGA/poly(varepsilon-caprolactone) (PCL) blended (w/w = 3/1) polymeric electrospun scaffolds with 0-30 wt% of nAp incorporation (n0-n30) were prepared. The obtained scaffolds were firstly evaluated by morphological, physical and chemical characterization, followed by an in vitro degradation study. Further, n0 and n30 in both virgin and 3-week pre-degraded status were subcutaneously implanted in rats, either directly or in stainless steel mesh cages, to evaluate in vivo tissue response. The results showed that the incorporation of nAp yields an nAp amount-dependent buffering effect on pH-levels during degradation and delayed polymer degradation based on molecular weight analysis. Regarding biocompatibility, nAp incorporation significantly improved the tissue response during a 4-week subcutaneous implantation, showing less infiltration of inflammatory cells (monocyte/macrophages) as well as less foreign body giant cells (FBGCs) formation surrounding the scaffolds. Similar cytokine expression (gene and protein level) was observed for all groups of implanted scaffolds, although marginal differences were found for TNF-alpha and TGF-beta at gene level as well as GRO-KC at protein level after 1 week of implantation. The results of the current study indicate that hybridization of the weak alkaline salt nAp is effective to control the in vivo adverse tissue reaction of PLGA materials, which is beneficial for optimizing final clinical application of different PLGA-based biomedical devices.