Micro- and nanoparticles delivery systems have been widely studied as vaccine adjuvants to enhance immunogenicity and sustain long-term immune responses. Polygonatum sibiricum polysaccharide (PSP) has been widely studied as an immunoregulator in improving immune responses. In this study, we synthesized and characterized cationic modified calcium carbonate (CaCO) microparticles loaded with PSP (PEI-PSP-CaCO, CTAB-PSP-CaCO), studied the immune responses elicited by PEI-PSP-CaCO and CTAB-PSP-CaCO carrying ovalbumin (OVA). Our results demonstrated that PEI-PSP-CaCO significantly enhanced the secretion of IgG and cytokines (IL-4, IL-6, IFN-γ, and TNF-α) in vaccinated mice. Additionally, PEI-PSP-CaCO induced the activation of dendritic cells (DCs), T cells, and germinal center (GC) B cells in draining lymph nodes (dLNs). It also enhanced lymphocyte proliferation, increased the ratio of CD4/CD8 T cells, and elevated the frequency of CD3 CD69 T cells in spleen lymphocytes. Therefore, PEI-PSP-CaCO microparticles induced a stronger cellular and humoral immune response and could be potentially useful as a vaccine delivery and adjuvant system.