Scaffolds are crucial to tissue engineering/regeneration. In this work, a technique combining a unique phase-separation process with a novel sugar sphere template leaching process has been developed to produce three-dimensional scaffolds. The resulting scaffolds possess high porosities, well connected macropores, and nanofibrous pore walls. The technique advantageously controls macropore shape and size by sugar spheres, interpore opening size by assembly conditions (time and temperature of heat treatment), and pore wall morphology by phase-separation parameters. The bioactivity of a macroporous and nanofibrous poly(L-lactic acid) (PLLA) scaffold was demonstrated by the bone-like apatite deposition throughout the scaffold in a simulated body fluid (SBF). Preincorporation of nanosized hydroxyapatite eliminated the induction period and facilitated the apatite growth in the SBF. Interestingly, the apatite growth primarily occurred on the surface of the pores (internal and external) but not the interior of the nanofibrous network away from the pore surface. It was also noticed that the macropore size did not affect the apatite growth rate, while the interpore opening size did. The compressive modulus also increased substantially when a continuous apatite layer was formed on the pore walls of the scaffold. The resulting composite scaffold mimics natural bone matrix with the combination of an organic phase (a polymer such as PLLA) and an inorganic apatite phase. The demonstrated bioactivity of apatite layer, together with well-controlled macroporous and nanofibrous structures, makes the novel nanocomposite scaffolds desirable for bone tissue engineering.