Acrylic bone cements (ABC) are materials widely used in orthopedics and biomedical applications. Several active compounds have been introduced to ABC formulations to improve their mechanical properties and bifunctionality. In this research, we studied the effect of the addition of chitosan (CS) microspheres and chitosan sheets on ABC formulations. For mechanical performance optimization, the compression strength was taken as a response variable using an extreme vertices mixing design with fraction by weight of CS and poly(methyl methacrylate) (PMMA) as the variable factors. According to the statistical analysis, the control samples (without CS), samples with 7% (wt.) of CS sheets, and samples with 17% (wt.) of CS spheres presented the best compression properties: 90.6 MPa and 95.6 MPa, respectively. The study of these formulations confirmed that CS spheres allow a higher amount of loading on the formulation, maintaining comparable compression strength. By 1H-NMR, it was observed that the residual monomer was similar in all wording. The hydrolytic degradation assay in simulated body fluid (SBF) determined that the sphere incorporation increased by 50% and 35% for the water uptake and weight loss values, respectively, when compared with the reported values with CS sheets. By morphological analysis via SEM, it was observed that the porosity increased considerably in the presence of CS spheres throughout the immersion time in SBF. The subdermal implant results demonstrated excellent compatibility between the cement studied and the biological environment.