Smallpox is an infectious disease caused by the variola virus, belonging to the Poxviridae family. It has a significant historical impact, with outbreaks spanning centuries and causing widespread morbidity and mortality. The disease is characterized by a distinctive rash with pustules, high fever, and systemic symptoms. Smallpox played a pivotal role in shaping world history, influencing the outcome of wars and contributing to population declines. In the 20th century, a global effort led to the successful eradication of smallpox, making it the first and only human disease eradicated through vaccination. The World Health Organization (WHO) launched an intensive vaccination campaign, utilizing the smallpox vaccine developed by Edward Jenner and later improved by Albert Calmette and Camille Guérin. The last known natural case of smallpox occurred in Somalia in 1977, marking a historic achievement in public health. Vaccination played a central role in the eradication campaign, emphasizing ring vaccination strategies and surveillance to identify and contain outbreaks. The success of smallpox eradication paved the way for the development of other vaccination programs and showcased the potential of coordinated global efforts in disease control.