The International Criminal Court said Gadhafi, his son Seif al-Islam Gadhafi and his intelligence chief Abdullah al-Sanoussi are wanted for orchestrating the killing, injuring, arrest and imprisonment of hundreds of civilians during the first 12 days of an uprising to topple Gadhafi from power, and for trying to cover up their alleged crimes.
The warrants will be sent to Libya, where Gadhafi remains defiantly entrenched.
Prosecutors said the three suspects should be arrested quickly "to prevent them covering up ongoing crimes and committing new crimes."
Gadhafi's regime rejected the court's authority even before the decision was read, accusing the court of unfairly targeting Africans while ignoring what it called crimes committed by NATO in Afghanistan, Iraq "and in Libya now."
After more than three months of fighting, it appears civil war is inevitable in Libya. The struggle between Gadhafi's regime and rebels trying to topple him from power after 42 years has now raged on for 101 days.
Even supported by NATO airstrikes, it has been slow going for the rebels. Still, they are making progress, not just to the east of the capital Tripoli, but to the south and to the west.
NATO has intensified its bombing raids in Libya in recent weeks. Feeling the heat, the regime has armed 1.2 million civilians with AK-47s in anticipation of a clash.
The Associated Press contributed to this story