Thomas Eric Duncan, who caught the virus in his native Liberia, was being kept in isolation in a Dallas hospital and receiving experimental drugs.
Earlier the US announced new screening measures at entry points to check travelers for symptoms of the virus.
More than 3,000 people have died and 7,500 infected, mostly in West Africa, in the worst Ebola outbreak yet.
“It is with profound sadness and heartfelt disappointment that we must inform you of the death of Thomas Eric Duncan this morning at 7:51 am,” a spokesman said in a statement.
The news came shortly after Secretary of State John Kerry urged all nations to boost their response to combat the virus.
“More countries can and must step up,” he said in a joint press conference with his British counterpart Philip Hammond.
The US has pledged as many as 4,000 troops to the region, while the UK is sending 750 military personnel to Sierra Leone.
Thomas Eric Duncan, who worked as a driver for a courier company, tested positive in Dallas, Texas, on September 30, 10 days after arriving on a flight from Monrovia via Brussels.
He become ill a few days after arriving in the US but after going to hospital and telling them he had been to Liberia he was sent home with antibiotics.
Four days later, Thomas Eric Duncan was placed in isolation but his condition continued to worsen and this week he was given an experimental drug.
Ten people he came into contact with are being monitored for symptoms.
Following Thomas Eric Duncan’s diagnosis, the first case of contagion outside that continent was confirmed in Spain, where nurse Teresa Romero, who treated an Ebola victim in Madrid, contracted the virus herself.
Spanish nurse Teresa Romero, is the first person known to have contracted the deadly virus outside West Africa.
Teresa Romero had treated two Spanish missionaries who later died from Ebola.
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