Demineralized bone matrices (DBMs) are widely used in bone replacement therapy. Bone tissue of either cancellous or cortical origin is decellularized, demineralized, and sterilized during processing, while retaining portions of native organic extracellular matrix (ECM) proteins that regulate cell-matrix interactions during bone repair. The ECM largely accounts for the distinct functions of cortical and cancellous bone. Differences in three-dimensional architecture and matrix density between cancellous and cortical bone may therefore affect ECM proteomic signatures and the resulting cellular microenvironment. In this study, ECM proteins were extracted from processed cancellous and cortical allografts at multiple processing steps and analyzed by quantitative mass spectrometry. We identified distinct extractable proteome signatures associated with bone metabolic functions. Cancellous grafts were enriched in proteins linked to inflammatory, coagulative, and immune-related processes, essential in early-phase bone healing and immune cell recruitment. Cortical grafts showed higher abundance of structural and matrix-organizing proteins linked to ECM organization and bone maturation, which are hallmarks of late-phase bone repair. Progressive processing reduces the number of differentially abundant proteins in both bone types. These findings are relevant for the selection, application, and quality assessment of DBM-based allograft products and their potential influence on the cellular microenvironment during bone regeneration.