Background: Therapeutic recombinant biological products are essential in modern medicine, but their immunogenicity remains a major concern for both clinical safety and therapeutic efficacy. Protein aggregation may occur during manufacturing, storage, transportation, and administration, potentially increasing immune recognition. Here, we have reviewed the mechanisms underlying aggregation-associated immunogenicity and summarized strategies for mitigating the associated risks. Methods: We integrated published evidence on therapeutic recombinant proteins, monoclonal antibodies, antibody–drug conjugates, peptide and glycoprotein hormones, and recombinant blood products. We focused on aggregation-induced structural changes, immune activation pathways, differences among product types and aggregation states, and approaches for controlling aggregation and mitigating immunogenicity. Results: Protein aggregation creates or reveals neoepitopes by disrupting the native conformational state, exposing previously buried hydrophobic regions, and generating nonnative interfaces. Aggregates may further promote innate and adaptive immune responses through repetitive epitope presentation, pattern-recognition receptor signaling, complement activation, cytokine release, dendritic-cell maturation, enhanced antigen presentation, and B-cell receptor cross-linking, ultimately increasing the likelihood of anti-drug antibody formation. Aggregate size and morphology, protein characteristics, formulation, storage conditions, administration route, and other biological factors influence the immunogenic potential of aggregates. Thus, effective risk reduction requires integrated control strategies, including molecular and structural optimization, formulation design, manufacturing-process control, appropriate storage and transportation, and sensitive analytical monitoring. Emerging artificial-intelligence approaches may further facilitate the prediction and design of low-immunogenicity biologics. Conclusions: Protein aggregation is a multifactorial determinant of immunogenicity. Controlling aggregation throughout the product lifecycle is essential to reduce immune-mediated risks and maintain safety, stability, and efficacy of therapeutic recombinant biological products.