"France, like the European Union, will not recognise this pseudo-consultation," Hollande told a joint press conference in Paris with Italian Prime Minister Matteo Renzi, a day before the referendum.
The French leader pledged EU sanctions against Russia if the situation did not "de-escalate" and said all efforts must be made to return to negotiation over Ukraine.
He said there was "no legal basis" for the vote in Crimea, a peninsula inhabited by two million mostly Russian speakers.
Kiev has denounced the Crimean referendum as illegal, but the pensinsula is widely expected to vote to split from Ukraine and join Russia after its lawmakers declared independence from Kiev earlier this month.
The referendum comes in direct response to three months of deadly protests that on February 22 toppled the pro-Kremlin president and brought to power a new European-leaning team in Kiev that threatens to shatter President Vladimir Putin's dream of rebuilding a post-Soviet empire.