The current study is a comparative assessment of the bone regeneration potentiality of bone substitutes composed of bioactive polymer–coated biphasic calcium phosphate (BCP) granules. The bone substitutes were primarily composed of multichanneled BCP granules, which were coated separately with biochemical polymer coatings, namely collagen, heparin, or polydopamine (PD), using chemical methods. The morphologic features and chemical structure of the granules and surface coatings were characterized by scanning electron microscopy and Fourier transform infrared spectroscopy, respectively. The biological characterizations in terms of cellular interaction with the bone substitutes in vitro (MTT assay and proliferation) and in vivo (bone regeneration efficacy) were performed and compared with uncoated BCP granules. It was found that PD-coated BCP granules were superior to the others with respect to promoting more rapid healing. Therefore, PD multichannel BCP granule system can be used as a promising injectable bone substitute for clinical applications.