CaCO3 hydrogel incorporation into Plaster of Paris (POP) formulations decreased the resorption rate of the POP after implantation in the body. Although an inflammatory process is required as part of wound healing, the accumulation and activation of inflammatory cells in the POP–hydrogel CaCO3 implant area needs to be controlled. Therefore, cinnamaldehyde, as an anti-inflammatory agent with a unique α, β-unsaturated aldehyde, was incorporated into the CaCO3 hydrogel. During the incorporation, both the lipophilic and hydrophilic sides of the cinnamaldehyde molecule can influence the physical and mechanical properties of the CaCO3 hydrogel, in which mechanical properties of a tissue engineering scaffold are important to fine tune cellular activity during implantation. On the other hand, as a 3-dimensional polymeric structure, crosslinking is needed for the CaCO3 hydrogel to stabilize and increase its molecular weight for better mechanical strength, and more resistance to heat, wear, and solvent attack. For that purpose, dehydrothermal treatment (DHT) was applied to the crosslink hydrogel system as a favorable crosslinking method to avoid the use of a chemical agent. In this study, 3 groups of hydrogels of CaCO3, namely DHT crosslinked, loaded with cinnamaldehyde, and loaded with cinnamaldehyde followed by DHT crosslinking were developed before being combined with POP in 50 wt%. To evaluate the effect of DHT to the final POP-cinnamaldehyde-loaded CaCO3 hydrogel properties and biocompatibility, scanning electron microscopy, contact angle, surface roughness, hardness, diametral tensile strength, and in vivo biocompatibility studies were conducted. It was observed that cinnamaldehyde with DHT treatment improved the POP–hydrogel CaCO3 properties and had good biocompatibility. Thus, POP-cinnamaldehyde-loaded CaCO3 hydrogel can be a promising bone substitute containing an anti-inflammatory agent.