Brushite cements are known for excellent osteoconductive and degradation properties, however, its widespread use is limited due to rapid setting time and poor mechanical properties. The eggshell derived calcium phosphates exhibits improved physical and biological properties due to the presence of biologically relevant ions. In this study, eggshell derived brushite cement (EB) was fabricated using β-tricalcium phosphate synthesized from eggshells. The presence of trace elements in EB prolonged its setting time. The size of brushite crystals in EB was found to be smaller than the pure brushite cement (PB) leading to increased initial compressive strength and higher in vitro degradation rate. The L6 and MG63 cell lines exhibited good biocompatibility with the cement at the end 72 h. In vivo studies of the cements were performed in rat calvarial defect model. Micro CT analysis showed faster degradation and accelerated bone formation in EB filled defect. Histological studies revealed infiltration of inflammatory cells into the implant site for both the cements till 6th week. However, inflammation was found to be significantly reduced at the 12th week in EB compared to PB leading to complete bone bridge formation. Multi-ion substituted EB seems to be a potential bone substitute material with a reasonable setting time for ease of handling, higher mechanical strength, minimal inflammatory response and higher bone regeneration. [Figure not available: see fulltext.]. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.