The election took place months after an annulled vote plunged the European Union and NATO member country into its worst political crisis in decades.
The ballot is seen as a test of the rise of Donald Trump-style nationalism in the European Union.
Ballots from nearly 98 per cent of voting stations showed Bucharest Mayor Nicusor Dan, 55, was in second place at around 21 per cent, behind Simion's 40 per cent.
They will meet in a runoff on May 18, if final results confirm the reading after diaspora votes are counted.
An independent running on an anti-corruption platform, Dan, 55, overtook former senator Crin Antonescu, 65, a centrist candidate backed by the three parties in the pro-western coalition government for his spot in the run-off.
A Simion victory could isolate the country, erode private investment and destabilise NATO's eastern flank, where Ukraine is fighting a three-year-old Russian invasion, political observers say.
It would also expand a cohort of Eurosceptic leaders in the EU that already includes the Hungarian and Slovak prime ministers at a time when Europe is struggling to formulate its response to Trump.
"This is not just an electoral victory, it is a victory of Romanian dignity. It is the victory of those who have not lost hope, of those who still believe in Romania, a free, respected, sovereign country," Simion said.
Benefiting from a wave of popular anger against mainstream leaders, Simion, 38, opposes military aid to neighbouring Ukraine, is critical of the EU leadership and says he is aligned with the US president's Make America Great Again movement.
The presidential election in Ukraine's neighbour is being closely watched by other European countries, since the post holds strong influence over foreign and security policy.
Sunday's vote came five months after a first attempt to hold the election was cancelled because of alleged Russian interference in favour of far-right frontrunner Calin Georgescu.
Georgescu was banned from running for president again and has been under investigation by the public prosecutor's office since February for making false statements about his campaign financing.
Simion says his aim is to ensure "justice" for Georgescu if he wins the election. He has not ruled out helping Georgescu into the office of prime minister.
with AP and reuters
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