The COVID-19 pandemic has underscored the importance of innovative protein design approaches to develop effective immunotherapeutics and vaccines capable of addressing the evolution of SARS-CoV-2 variants. This study focuses on the rational design of a SARS-CoV-2 multi-epitope protein that integrates immunogenic epitopes from the structural proteins Spike, Envelope, Membrane, and Nucleocapsid, linked by rigid and flexible connectors. This construct was developed to stimulate a comprehensive and durable immune response by targeting conserved epitopes, aiming to provide robust protection against prevalent circulating variants, including Omicron. Epitope selection was performed through immunogenicity and MHC binding analyses using the T Cell Epitopes - MHC Binding Prediction tool (IEDB Analysis Resource) and VaxiJen v2.0. Additionally, the epitopes were evaluated for physicochemical parameters, such as molecular weight and isoelectric point, as well as for the presence of N- and O-glycosylation sites using ProtParam and the NetNGlyc and NetOGlyc tools. The final protein sequence was further analyzed for immunogenicity, toxicity, and allergenicity using ProtParam and AllerCatPro 2.0, ensuring the construct's safety and immunogenic profile. Three-dimensional modeling of the protein was conducted using the I-TASSER tool, which integrates threading, ab initio modeling, and structural refinement. The generated model was validated for structural stability and alignment with the predicted epitopes, indicating a conformation potentially effective for immune response induction. The final protein sequence demonstrated appropriate physicochemical properties for expression in eukaryotic systems, which is essential for correct epitope presentation to host immune systems. Immunogenicity analyses indicated that the construct includes highly conserved epitopes, particularly within the S and N proteins, enhancing the potential for cross-protection against variants. The multi-epitope protein was confirmed to be non-toxic and non-allergenic, with a positive immunogenicity score. The validated model from I-TASSER exhibited a conformation that preserves the accessibility of immunogenic epitopes, which is essential for future interaction with neutralizing antibodies. As conclusion, this rationally designed multi-epitope protein construct is a promising tool for development of immunotherapies and vaccines against COVID-19. By focusing on conserved and variant-relevant epitopes, this approach could offer a broad and durable immune response with potential to adapt to emerging variants, significantly contributing to long-term preventive strategies against SARS-CoV-2.