Turkey and the U.S. immediately condemned the attack and U.S. officials urged Americans to stay away from all U.S. diplomatic offices throughout Turkey.
A Turkish woman was also seriously wounded and two other guards sustained lighter wounds in the 1:15 p.m. blast in the Turkish capital, Interior Minister Muammer Guler told reporters.
There was no immediate claim of responsibility, but Guler said "preliminary information" obtained by police indicated that the bomber was likely connected to a domestic left-wing militant group. He did not elaborate.
A police official, meanwhile, told The Associated Press that the bomber is most likely a suspected member of the outlawed Revolutionary People's Liberation Party-Front, or DHKP-C. He spoke on condition of anonymity because he was not permitted to speak to the press.
The group has been designated a terrorist organization by the United States but had been relatively quiet in recent years.
Friday's explosion occurred inside the security checkpoint at the side entrance to the U.S. embassy, which is used by staff. A guard standing outside the checkpoint was killed while the two guards that were wounded "were standing in a more protected area," Guler said.
Police and ambulances swarmed the area and authorities immediately cordoned it off. Forensic investigators in white outfits and gloves combed the site.
TV footage showed the embassy door blown off its hinges. The blast also shattered the windows of nearby businesses, littering debris on the ground and across the road. The inside of the embassy did not appear to be damaged.
Television footage also showed what appeared to be a U.S. marksman in a helmet and body armor surveying the area from the roof of an embassy building.
The U.S. Embassy building in Ankara is heavily protected and located near several other embassies, including that of Germany and France. The Hurriyet newspaper said staff at the embassy took shelter in "safe room" inside the compound soon after the explosion.
In a statement, the U.S. Embassy thanked Turkey for "its solidarity and outrage over the incident."
U.S. Ambassador Francis Ricciardone declared that the U.S. and Turkey "will continue to fight terrorism together" and described the U.S. Embassy compound as secure.
"From today's event, it is clear that we both suffer from this terrible, terrible problem of today's world. We are determined after events like this even more to cooperate together until we defeat this problem together," he said.
Turkish Prime Minister Recep Tayyip Erdogan echoed that sentiment, saying the attack aimed to disturb Turkey's "peace and prosperity" and demonstrated a need for international cooperation against terrorism.
"We will stand firm and we will overcome this together," he said.
In Washington, State Department spokeswoman Victoria Nuland said U.S. officials were "working closely with the Turkish national police to make a full assessment of the damage and the casualties, and to begin an investigation."
Turkish Foreign Minister Ahmet Davutoglu vowed that Turkey would spare no effort in protecting diplomatic facilities.
"We have always shown great sensitivity to the protection of foreign missions and we will continue to do so," he said.
The injured woman was 38-year-old Didem Tuncay, a respected television journalist who until recently had worked for NTV television. A hospital official said she was "not in a critical condition."
Ricciardone visited Tuncay in the hospital and told reporters outside that he had invited her to the U.S. Embassy for tea.
He also paid tribute to the Turkish guard who was killed, calling him a "Turkish hero" who died while defending U.S. and Turkish staff at the Embassy.
Americans in Turkey were warned to avoid visiting the embassy or U.S. consulates in Istanbul and Adana until further notice and were told to register on the State Department's website.
"The Department of State advises U.S. citizens traveling or residing in Turkey to be alert to the potential for violence, to avoid those areas where disturbances have occurred, and to avoid demonstrations and large gatherings," said a statement issued by the U.S. Consulate in Istanbul.
British Foreign Secretary William Hague condemned Friday's attack "in the strongest terms" and said Turkey and the U.S. will get the U.K.'s full support as they seek to hold those responsible to account.
U.S. diplomatic facilities in Turkey have been targeted previously by terrorists. In 2008, an attack blamed on al-Qaida-affiliated militants outside the U.S. Consulate in Istanbul left three assailants and three policemen dead.
Elsewhere, terrorists attacked a U.S. mission in Benghazi, Libya, on Sept. 11 last year, killing U.S. Ambassador Chris Stevens and three other Americans. The attackers in Libya were suspected to have ties to Islamist extremists, and one is in custody in Egypt.
In past years, the DHKP-C group has spearheaded hunger strikes against Turkish prison conditions that led to the deaths of dozens of inmates. The protesters opposed a maximum security system in which prisoners were incarcerated in one or three-inmate cells instead of large wards that used to house up to 100 inmates.
In September, police said a leftist militant threw a hand grenade and then blew himself up outside a police station in Istanbul, killing a police officer and injuring seven others. Police identified the bomber as a member of the DHKP-C, which has claimed responsibility for assassinations and bombings since the 1970s.
In 2008, Turkish police said they had foiled a bomb plot by DHKP-C against some U.S. companies in Turkey.
Turkey has also seen attacks linked to homegrown Islamic militants tied to al-Qaida. In a 2003 attack on the British consulate in Istanbul, a suspected Islamic militant rammed an explosive-laden pickup truck into the main gate, killing 58 people, including the British consul-general.
Turkey has also been deeply affected by the civil war in neighboring Syria, and has become a harsh critic of President Bashar Assad's regime there. The war has left at least 60,000 people dead, according to the U.N., and Turkey is sheltering tens of thousands of Syrian refugees.
The first of six Patriot missile batteries being deployed to Turkey to protect the country against attack from Syria was just declared operational and placed under NATO command. Others are expected to become operational in the coming days.
Associated Press writer Ezgi Akin contributed to the report.