This paper reports the use of waste oyster shells as a novel biofiller for hot-mix asphalt (HMA) pavement applications. The effects of different fractions (e.g., 0, 5, 10, 15 wt %) of oyster shell powder (OSP) on the bitumen performance were investigated. The chemical properties of unfilled and OSP-filled asphalts were characterized by means of thin layer chromatography-ionization detection (TLC-FID), Fourier transform-infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Thermal characteristics were examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Physical and rheological properties were assessed through penetration, softening point, ductility, and dynamic shear rheometer (DSR) tests. Results showed that OSP addition increased the resins content, as well as the stiffness of blends. No obvious reactions have occurred between the filler and the asphalt. A higher dose of OSP altered the morphology of the binder, whereas lower and intermediate doses improved its thermal stability and enhanced its low-temperature, rutting, and fatigue performances with respect to the plain asphalt. Overall, the waste oyster shells could be used as filler substitute, not only to improve the quality of road pavements but also to reduce the cost of their construction and solve the waste disposal problems.