Viruses exhibit remarkable diversity in genome size, ranging from compact RNA genomes of a few kilobases to large DNA or RNA genomes exceeding 30 kilobases. The genome size not only dictates the coding capacity and complexity of viral replication strategies but also influences viral interactions during coinfection. In particular, competition between small- and large-genome viruses within the same host environment has emerged as a key theme in understanding viral pathogenesis and evolution. This study highlights the contrasting interactions of small-genome viruses, such as Newcastle disease virus (NDV) and Influenza A virus (IAV), with large-genome viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human papillomavirus type 1 (HPV-1). While SARS-CoV-2 and HPV-1 possess expansive coding repertoires enabling modulation of host immune pathways and long-term persistence, NDV and IAV rely on streamlined genomes that drive rapid replication and acute pathogenicity. Evidence suggests that during coinfection, small-genome viruses often outcompete larger-genome viruses at the replication level, due to faster life cycles and higher burst sizes. Conversely, large-genome viruses employ sophisticated immune evasion mechanisms and host-cell reprogramming to sustain infection, which may suppress or delay replication of smaller competitors. These dynamics underscore the balance between replication efficiency and immune modulation as central determinants of viral dominance. Understanding these competitive interactions is crucial for predicting disease outcomes in natural coinfections and for harnessing oncolytic or vaccine-based applications, where deliberate viral interference may be advantageous. By integrating comparative virology with host–pathogen interaction studies, we propose that genome size serves as a fundamental parameter shaping viral competition, persistence, and pathogenesis. These insights provide a framework for future investigations into mixed viral infections and their implications for public health and therapeutic strategies.