Enveloped viruses especially Coronaviruses, Influenza viruses, and Human Immunodeficiency viruses pose a great risk to the human and animal populations. These viruses cause diseases of clinical and socio-economic importance with the help of their spike protein. Coronaviruses affect the respiratory, gastrointestinal tract, and nervous system and the influenza virus affects the respiratory system while the Human Immunodeficiency Virus affects multiple systems as it invades and destroys immune cells. We aimed to review the role of spike protein in the four viruses and their effects on disease severity. We searched through online publication databases such as PubMed, Google Scholar, and Scopus to retrieve 150 scientific published articles using keywords like ‘Spike Protein’, ‘Viruses’, ‘Infection’, and ‘Diseases’. A total of 100 articles were used to write this article. Spike protein is an essential structure in viruses that causes infections and diseases in humans and animals. Targeting this protein in the development of antiviral drugs and vaccines should be a major concern.