Objectives: To evaluate the bone regeneration potential of a new membrane fabricated with polyglycolide acid (PLGA) after being treated with oxygen plasma (PO2), and/or being functionalized with silicon dioxide (SiO2) or titanium dioxide (TiO2) nanoparticles. Methods: Bone defects (5 mm × 3 mm) were produced on the top of 3 experimentation rabbits’ skulls and were covered with variously modified PLGA scaffolds. After the animals were sacrificed, neoformed bone (%), mineralized bone (mm), bone resorption (%), osteoclasts/mm2, and intensity of osteosynthetic activity, were assessed under microscope. Results: The following groups were formed depending on the type of membrane: PLGA (control); PLGA/PO2; PLGA/SiO2; PLGA/TiO2; PLGA/PO2/SiO2; and PLGA/PO2/TiO2. The histological sections showed bone layers in advanced stages of formation. The highest percentages of neoformed bone corresponded to PLGA/PO2/SiO2 membranes (59.07%; p = 0.31) followed by PLGA/PO2 barriers (50.27%). The controls showed the lowest mineralization (13.89 mm; p = 0.24). PLGA/TiO2 scaffolds exhibited the least bone resorption (4.45%; p = 0.77) and osteoclasts/mm2 (1.58; p = 0.86). PLGA/SiO2 and PLGA/TiO2 membranes stimulated the maximum osteosynthetic activity. Conclusions: The treatment of PLGA barriers with PO2 increased bone regeneration in rabbits. When comparing the effect of PO2/SiO2 and PO2/TiO2, higher percentages of neoformed bone were encountered after silicon-dioxide coating. Clinical significance: The incorporation of SiO2 nanoparticles onto PO2-treated PLGA membranes was the most promising technique out of those investigated to promote bone formation in rabbits. The addition of SiO2 or TiO2 layers to PLGA substrates may stimulate the osteosynthetic activity, which might be useful to restore bone dimensions in preparation for naturally appearing dental prostheses.