In recent years, research in the development of polymeric materials for orthopedic implants has become ever more important because the global demand of biocompatible implants has been steadily increasing. Bioinert polyetheretherketone (PEEK) is typically reinforced with bioactive hydroxyapatite microparticles. However, the tensile strength of conventional PEEK/hydroxyapatite microcomposites falls sharply with increasing filler loading. To address low strength and high filler loading issues, nanohydroxyapatite rods (nHA) and carbon nanofibers (CNF) were employed to reinforce PEEK. In this study, molded-grade PEEK pellets, nHA and CNF fillers were melt-mixed and injection molded to form PEEK/nHA and hybrid PEEK/nHA–CNF nanocomposites. The tensile and thermal properties, as well as the bioactivity and biocompatibility of such nanocomposites, were investigated. Tensile test results showed that elastic modulus of PEEK/nHA nanocomposites increases with increasing nHA content. The PEEK/9.3 vol% nHA nanocomposite exhibited higher tensile strength than that of a conventional HAPEX microcomposite. Thermogravimetric measurements indicated that the nHA addition improves the thermal stability of PEEK. Thus, the PEEK/9.3 vol% nHA nanocomposite that had good mechanical, thermal and biological performances was an attractive biomaterial for use in maxillofacial surgery. Furthermore, the tensile property of the PEEK/15 vol% nHA–1.9 vol% nHA nanocomposite compared favorably with that of human cortical bones. The results of biomineralization, alkaline phosphatase (ALP), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) assays also showed that the PEEK/15 vol% nHA and PEEK/15 vol% nHA–1.9 vol% CNF nanocomposites exhibited excellent bioactivity and biocompatibility. The ALP assay showed good activity of osteoblast cells on the composite specimens with high nHA content. Moreover, CNF addition further increased the ALP activity of PEEK/15 vol% nHA nanocomposites. The PEEK/15 vol% nHA–1.9 vol% CNF composite, with enhanced tensile strength and excellent biocompatibility, shows large potential for load-bearing implant applications.