Determining the "worst" disease in history depends on whether you measure by total death toll or the percentage of the population killed in a short time. By sheer numbers, Tuberculosis (TB) is often considered the deadliest, having killed an estimated 1 billion people over the last two centuries alone. However, in terms of sheer devastation, the Black Death (Bubonic Plague) in the 14th century is the most infamous, killing an estimated 75 to 200 million people—roughly 30% to 60% of Europe's entire population at the time. Another contender is Smallpox, which is estimated to have killed 300 to 500 million people in the 20th century alone before being eradicated in 1980. The 1918 Spanish Flu was also horrific, claiming 50 to 100 million lives in just two years. In 2026, historians and scientists also point to Malaria as a "slow-motion" catastrophe that has likely killed half of all humans who have ever lived, though such ancient statistics are difficult to verify precisely. Each of these diseases fundamentally reshaped human society, economy, and genetics.