Background: A promising strategy to enhance bone regeneration is the use of bioactive materials doped with metallic ions with therapeutic effects and their combination with active substances and/or drugs. The aim of the present study was to investigate the osteogenic capacity of human periodontal ligament cells (hPDLCs) in culture with artemisinin (ART)-loaded Ce-doped calcium silicate nanopowders (NPs); Methods: Mesoporous silica, calcium-doped and calcium/cerium-doped silicate NPs were synthesized via a surfactant-assisted cooperative self-assembly process. Human periodontal ligament cells (hPDLCs) were isolated and tested for their osteogenic differentiation in the presence of ART-loaded and unloaded NPs through alkaline phosphatase (ALP) activity and Alizarine red S staining, while their antioxidant capacity was also evaluated; Results: ART promoted further the osteogenic differentiation of hPDLCs in the presence of Ce-doped NPs. Higher amounts of Ce in the ART-loaded NPs inversely affected the mineral deposition process by the hPDLCs. ART and Ce in the NPs have a synergistic role controlling the redox status and reducing ROS production from the hPDLCs; Conclusions: By monitoring the Ce amount and ART concentration, mesoporous NPs with optimum properties can be developed towards bone tissue regeneration demonstrating also potential application in periodontal tissue regeneration strategies.