The bombing occurred two days before George Bush, the US president, was to visit Pakistan.
President Bush, currently in New Delhi, condemned Thursday's attack and said "terrorists and killers" would not prevent him from going to Pakistan on the final leg of a tour of South Asia.
The attack took place in the car park of the Marriott hotel in Karachi, about 20 metres from the consulate gate, Mushtaq Shah, a police official, said.
The explosion shattered windows at the consulate, hotel and other nearby buildings, and destroyed at least 10 cars.
Niaz Sadiqui, Karachi's police chief, said the attacker wanted to hit the US consulate, but a Pakistani paramilitary guard saw him and tried to stop him, so he drove his car into the diplomat's vehicle instead.
The guard was also killed in the blast.
The bombing damaged nearby
buildings and cars
"We have reached the conclusion that it was a suicide attack, and we have found body parts of the attacker," said Sadiqui.
He added that police had found important clues and would soon solve the case, but declined to disclose details.
The diplomat's car was blown into the air, across a concrete barrier and into the grounds of the hotel.
The driver, a Pakistani working for the consulate, also died.
The other fatality was an unidentified woman. One male body, with part of its head missing, was flung by the blast onto the second storey of the hotel's exterior.
A counter-terrorism official who declined to be named, said high-intensity explosives were used in the blast - the most powerful blast he had seen in Karachi.
Witnesses said the explosion triggered a second, smaller blast, possibly of a burning car.
Some 52 people were injured, including a young Moroccan girl who was hit by debris, Salahuddin Haider, the provincial government spokesman, said.
Nida Emmons, a spokeswoman for the US embassy in Islamabad, confirmed an American and Pakistani employee of the consulate were killed, but would not give their names.
She said they were still investigating if any other consulate staff were hurt.
Among the dead was a guard who
tried to stop the bomber
The bombing left a crater 2.5m wide and more than 60cm deep.
Mohammed Ali, who sells cigarettes nearby, said the first explosion occurred around 9am local time, knocking him down and flattening his wooden stall.
"Seconds later there was another explosion. We ran away to save our lives," said Ali. "The explosions set cars on fire and there was smoke all around... I thought the explosions would burst my ear drums."