About 93% of Crimean voters have backed joining Russia and seceding from Ukraine, exit polls have suggested.
Crowds of pro-Moscow voters celebrated in the main city of Simferopol, and Crimea's pro-Russia leader said he would apply to join Russia on Monday.
But many Crimeans loyal to Kiev boycotted the referendum, and the EU and US condemned it as illegal.
Pro-Russian forces took control of Crimea in February after Ukraine's pro-Moscow president was overthrown.
On the ballot paper, voters were asked whether they would like Crimea to rejoin Russia.
A second question asked whether Crimea should return to its status under the 1992 constitution, which would give the region much greater autonomy.
There was no option for those who wanted the constitutional situation to remain unchanged.
Ethnic Russians make up 58.5% of the region's population, and many of them were expected to vote for joining Russia.
One voter, Olga Koziko, told the BBC that she was voting for secession because she did not want to be governed by "those Nazis who came to power in Kiev".
"Russia will defend us and protect us," the schoolteacher said.
There are 1.5 million eligible voters and election officials put the turnout in Sunday's vote at more than 80%.
Ethnic Tatars, who make up 12% of the population, mostly boycotted the election.
Sergei Aksyonov, who was installed as Crimea's regional government leader after Russia's military takeover, said a session of parliament would take place on Monday.
"The Supreme Soviet of Crimea will make an official application for the republic to join the Russian Federation at a meeting on March 17," he said on Twitter after the vote.
But White House spokesman Jay Carney condemned the vote as "dangerous and destabilising" and said it would have "increasing costs for Russia".
The US has previously threatened to impose sanctions on Russia.
The European Union said the vote was "illegal and illegitimate and its outcome will not be recognised".
EU foreign ministers are due to meet on Monday and are expected to consider imposing sanctions on Russian officials.
Away from the Crimea region, unrest continued in the south-east Ukrainian city of Donetsk.
Pro-Russian protesters stormed the prosecutor's building shouting "Donetsk is a Russian city", and then broke into the local security services headquarters for the second time in two days.
They later dispersed but promised to return on Monday.
The protesters are demanding that the prosecutor release a pro-Russian leader, Pavel Gubarev.
The Kremlin said President Vladimir Putin had told German Chancellor Angela Merkel by phone he was concerned by escalating tensions in Donetsk, blaming "radical groups" which had the consent of Kiev.
Mr Putin told Mrs Merkel that Sunday's referendum was legal and Moscow would respect the result.
The German chancellor's spokesman said she had proposed expanding the presence of international observers from the OSCE in eastern Ukraine and that Mr Putin had welcomed the plan.
Ukrainian Prime Minister Arseniy Yatsenyuk warned that the authorities would track down separatist "ringleaders".
"We will find all of them - if it takes one year, two years - and bring them to justice and try them in Ukrainian and international courts," he said.
In other developments:
- Ukraine's acting Defence Minister Ihor Tenyukh said a temporary truce had been agreed with Russia until 21 March in which the blockade of Ukrainian military units in Crimea would be lifted
- Kiev accused Russian forces of seizing the village of Strilkove, just north of Crimea, describing it as a "military invasion"
Russia on Saturday vetoed a draft UN resolution criticising the vote - the only Security Council member to vote against it.
Moscow's main ally China abstained, ensuring Russia's isolation.
The Crimean region was part of Russia until 1954 and Russia's Black Sea fleet is based in Ukrainian ports.
But Moscow has signed agreements promising to uphold Ukraine's territorial integrity.