The co-circulation of dengue virus (DENV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in endemic regions poses significant immunological challenges, particularly in the context of cross-reactivity and vaccine design. Leveraging an in-silico pipeline, this study sought to identify conserved antigenic determinants between DENV serotype 1 (DENV-1) and SARS-CoV-2 that may underlie molecular mimicry and immunological cross-reactivity. Viral protein sequences were obtained from UniProt, structurally modeled via SWISS-MODEL, and aligned using PRALINE. Conserved regions were mapped and visualized using PyMOL to identify accessible surface-exposed epitopes. Strikingly, up to 42% sequence identity was observed between DENV-1 polyproteins and SARS-CoV-2 proteins, including the nucleoprotein (N), spike (S), and nonstructural proteins NS7a and NS7b. Several conserved patches displayed surface accessibility, reinforcing their potential to elicit cross-reactive B or T cell responses. These findings highlight a critical concern in co-endemic settings: pre-existing DENV immunity could alter the outcome of SARS-CoV-2 infection or vaccination through heterologous immune responses, potentially contributing to antibody-dependent enhancement (ADE) or atypical inflammatory profiles. From an immunotherapeutic perspective, the identification of shared epitopes underscores the need for precision design in vaccines and monoclonal antibody therapies to avoid unintended immunopathology. While this bioinformatic study provides a foundational framework for predicting cross-reactive epitopes, experimental validation using serological assays, neutralization tests, and T cell activation studies are imperative. Ultimately, a deeper understanding of DENV–SARS-CoV-2 molecular mimicry may inform the development of safer and more effective immunotherapeutic strategies in regions burdened by both pathogens.