Presiding Judge Sanji Monageng said there were "reasonable grounds to believe" that Gaddafi and his son were both "criminally responsible as indirect co-perpetrators" for the murder and persecution of civilians.
The fact that the trio are now internationally wanted suspects could complicate efforts to mediate an end to the fighting in Libya.
The court's authority was rejected by the Libyan government before the verdict was given. They claimed the court had unfairly targeted Africans while ignoring "crimes" committed by Nato in Afghanistan, Iraq and Libya.
"The ICC has no legitimacy whatsoever. All of its activities are directed at African leaders," government spokesman Moussa Ibrahim said.
Foreign Secretary William Hague said: "I welcome the ICC judges' decision to issue arrest warrants for Col Muammar Gaddafi, Saif al Islam and Abdullah al Sanoussi.
"These individuals are accused of crimes against humanity and should be held to account before judges in a criminal court.
"The UK will continue to strongly support the ICC and calls upon the Libyan government to co-operate fully with the ICC investigation.
"The warrants further demonstrate why Gaddafi has lost all legitimacy and why he should go immediately. His forces continue to attack Libyans without mercy and this must stop."
ICC prosecutor Luis Moreno-Ocampo began an investigation into the activities of Col Gaddafi's regime following a referral by the United Nations Security Council.
His submissions to the ICC alleged Gaddafi had a personal hand in planning and implementing "a policy of widespread and systematic attacks against civilians and demonstrators and dissidents in particular."
"Gaddafi's plan expressly included the use of lethal force against demonstrators and dissidents," the submission said.
Meanwhile, Musa Kusa, Col Gaddafi's former intelligence officer, has been found living in a luxury Qatari hotel following his departure from Britain in April.
He is believed to have been living for several weeks in a 17th-floor penthouse suite at the Four Seasons Hotel in Doha.
He has been in the Gulf state since leaving Britain for talks there, and has the protection of a team of Qatari minders.
At the time, officials said Mr Kusa was likely to return to the UK because his grandchildren live there.
But it is now unclear whether he does intend to return, and he has reportedly refused to be drawn on the matter.
The former foreign minister arrived in the UK in March after defecting from Col Gaddafi's regime .
He was deputy head of the Libyan intelligence service at the time of the Lockerbie bombing in 1988, but has always denied the country was behind the atrocity.
While in Britain, he was questioned by Scottish police about the bombing. His departure just two weeks later infuriated victims' families.
A Foreign Office spokesman said: "He is a private individual who is free to travel to and from the UK. We don't provide a running commentary on his movements or current activities."
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