The White House said the murder of former Communist Party leader George Hawi was part of a pattern of targeted political assassinations to intimidate the Lebanese people.
United Nations Secretary General Kofi Annan also condemned the killing, saying it underscored UN support for the independence and sovereignty of Lebanon.
It was a stance repeated by Britain’s Foreign Office, which called for a “full, thorough, and transparent investigation”.
“These are not random killings, these are targeted assassinations of political figures,” said White House spokesman Scott McClellan.
While he didn’t explicitly blame Syria, Mr McClellan said the country’s “long and continued presence inside Lebanon has created an environment of intimidation and political repression” and should end immediately.
US Secretary of State Condoleezza Rice had a similarly blunt message, warning Damascus to “Knock it off.”
While she admitted she didn’t know who detonated the bomb, Ms Rice said: “There is a context and an atmosphere of instability. Syria’s activities are part of that context and a part of that atmosphere.”
The comments constitute Washington’s most explicit accusations of Syrian interference in Lebanese affairs since Damascus pulled its remaining troops out of the country in April, ending a 29-year presence.
The Bush administration has questioned whether Syria has withdrawn all its intelligence officers as well as expressing concern about the possible existence of a “hit list” of anti-Syrian figures targeted for assassination.
“Their military forces, their visible forces are gone but they are clearly still acting in Lebanon,” said Ms Rice.
“I think that the Syrians have got to look at what they are doing and they’ve got to stop whatever they are doing there that is causing destabilisation,” she added.
Mr Hawi’s assassination was the second of an anti-Syrian figure in Beirut this month. Newspaper columnist Samir Kassir was killed on June 2 when a similar explosion destroyed his car outside his home.
After Mr Kassir’s killing, the US said it had information about a Syrian hit-list targeting Lebanese leaders.
Damascus denied the claim and denounced Mr Hawi’s killing.
The latest bombing came after Lebanon completed a round of parliamentary elections, the country’s first polls since the Syrian military pullout.
It was convincingly won by an anti-Syrian alliance headed by Saad Hariri, the son of former Prime Minister Rafiq Hariri.
The murder of the elder Hariri in February plunged Lebanon into political turmoil but ultimately led to the Syrian pullout.