Mucosal surfaces are dynamic immunological interfaces that play a critical role in maintaining host defense and microbial homeostasis. Disruptions in the interaction between the mucosal immune system and its commensal microbiota have been associated with the onset of several diseases, including inflammatory bowel disease, asthma, and bacterial vaginosis. This review examines recent advances in nanoparticle (NP)-based strategies aimed at modulating mucosal immunity and restructuring microbial communities. It highlights how organic and inorganic NPs such as polysaccharide-based carriers, lipid NPs, and metallic nanomaterials enhance the delivery and stability of probiotics, prebiotics, and synbiotics, and facilitate targeted immunomodulation across gastrointestinal, respiratory, and female reproductive mucosal tissues. NP-based strategies are particularly emphasized for their ability to penetrate mucus barriers, facilitate microbial colonization, modulate cytokine activity, and enhance the restoration of epithelial barrier function. Disease-specific applications, including NP-based therapies for colitis, respiratory inflammation, and vaginal dysbiosis, are also discussed. In addition, this review outlines current challenges related to biosafety, targeting specificity, and clinical translation, and suggests future directions for research. Altogether, NP platforms offer a promising avenue for the precise modulation of mucosal immunity and microbiota, with significant potential in the prevention and treatment of mucosal-associated diseases.