The answer depends on whether you’re asking about overdose deaths or total deaths from long-term use. For overdoses, synthetic opioids like fentanyl kill more people than any other drug, responsible for 47,735 deaths in the United States in 2024 alone. But if you zoom out to include all causes of death linked to a substance, tobacco and alcohol each kill far more people worldwide than any illicit drug.
Fentanyl Leads All Overdose Deaths
In 2024, 79,384 people died from drug overdoses in the United States. Synthetic opioids other than methadone, a category dominated by illicitly manufactured fentanyl, accounted for 47,735 of those deaths. That makes fentanyl responsible for roughly 60% of all drug overdose fatalities in the country. No other single substance comes close.
Fentanyl’s danger comes from its extreme potency. A lethal dose can be as small as two milligrams, roughly the size of a few grains of salt. It’s often mixed into counterfeit pills or other drugs like cocaine and methamphetamine, meaning people sometimes take it without knowing. The drug kills by shutting down breathing. It acts on receptors throughout the brainstem that control respiratory rhythm, slowing the rate and depth of each breath until breathing stops entirely. A region deep in the brainstem called the preBötzinger Complex, which generates the basic breathing rhythm, is particularly vulnerable to opioid suppression.
Behind fentanyl, the other major contributors to overdose deaths in 2024 were methamphetamine and related stimulants (28,722 deaths), cocaine (21,945 deaths), and natural opioids like prescription painkillers (7,989 deaths). Heroin, once the face of the opioid crisis, was involved in just 2,743 deaths, a fraction of its peak years.
Most Overdoses Involve Multiple Drugs
A single drug rarely tells the full story of an overdose death. Between January 2021 and June 2024, 59% of all overdose deaths in the U.S. involved a stimulant, and 43% involved both a stimulant and an opioid together. Among deaths that involved cocaine, 79% also involved an opioid. Among methamphetamine deaths, 69% did. This mixing, sometimes intentional and sometimes not, makes fentanyl even more lethal because it amplifies the danger of whatever else is in a person’s system.
Newer synthetic opioids called nitazenes are also appearing in the drug supply. Some analogs are significantly more potent than fentanyl. Tennessee documented 42 nitazene-involved overdose deaths in 2021, up from 10 the year before. Those numbers are likely undercounted because standard toxicology panels often don’t test for them.
Who Is Most at Risk
Adults ages 35 to 44 had the highest overdose death rate in 2024 at 44.2 per 100,000 people, followed closely by 45- to 54-year-olds at 41.0 per 100,000. The youngest adults, ages 15 to 24, had the lowest rate at 8.5 per 100,000. One notable trend: while overdose rates dropped across all age groups from 2023 to 2024, the decline was smallest among adults 65 and older, who saw their rate fall only from 14.7 to 13.4 per 100,000.
Increases in stimulant-involved deaths over recent years have been largest among American Indian or Alaska Native and Black or African American populations, driven primarily by combinations of stimulants and opioids.
Alcohol Kills More People Than All Illicit Drugs Combined
If you count every death a substance causes, not just acute overdoses, alcohol surpasses all illegal drugs by a wide margin. Excessive drinking kills about 178,000 Americans per year, more than double the 79,384 who died from drug overdoses in 2024. About two-thirds of those alcohol deaths (roughly 117,000) come from chronic conditions that develop over years of drinking: liver disease, heart disease, and several types of cancer. The remaining third, around 61,000, come from acute causes like car crashes, alcohol poisoning, and alcohol-involved drug overdoses.
Globally, the World Health Organization estimates 2.6 million deaths per year are attributable to alcohol, compared to 600,000 from all other psychoactive drugs combined. Men account for the vast majority of both categories.
Tobacco Still Kills More Than Any Other Substance
Tobacco is the deadliest drug on Earth by total body count. The WHO reports that tobacco kills more than 7 million people every year worldwide, including an estimated 1.6 million nonsmokers exposed to secondhand smoke. In the United States alone, smoking causes roughly 480,000 deaths annually. These deaths come primarily from lung cancer, chronic obstructive pulmonary disease, heart disease, and stroke.
Tobacco doesn’t cause overdoses in the traditional sense, which is why it often gets left out of conversations about drug deaths. But nicotine is one of the most addictive substances known, and the long-term damage from inhaling combustion products is unmatched by any other widely used drug. The gap between tobacco and everything else isn’t even close: tobacco kills roughly 2.7 times as many people globally as alcohol and more than 10 times as many as all illicit drugs combined.
Putting the Numbers in Context
The substance that “causes the most deaths” shifts depending on the timeframe you care about. Fentanyl is the most dangerous drug for a single encounter. A tiny miscalculation in dose can stop your breathing within minutes. Alcohol is the most dangerous legal drug when measured by total annual deaths, driven by both chronic disease and acute incidents. And tobacco, used exactly as intended by its manufacturers, kills more people than any other substance on the planet.
U.S. overdose deaths did decline from 2023 to 2024, dropping from over 100,000 to about 79,000. That 21% decrease is the largest year-over-year drop in recent memory, driven partly by wider availability of the opioid-reversal medication naloxone and shifts in the drug supply. But 79,384 deaths is still a staggering number, and synthetic opioids remain the primary driver.