Ballots from 50 per cent of voting stations showed former senator Crin Antonescu, 65, in second place, with 23 per cent, behind Simion's 42 per cent.
In third place was Bucharest Mayor Nicusor Dan, 55, at 16 per cent. The top two candidates will meet in a runoff on May 18.
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.
"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.
Antonescu, 65, absent from politics for a decade, wants to continue Romania's substantial role in supporting Ukraine, and is well known by the electorate.
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, since banned from standing again.
Simion voted alongside Georgescu, who called the election a "fraud" and urged people to take their country back.
As dozens of people thronged outside the voting station chanting "Calin for president", Simion said his vote was "to restore democracy".
"It's possible the diaspora vote will be enough to push Dan into the run-off," said Sergiu Miscoiu, a political science professor at Babes-Bolyai University.
"But Dan may have a harder time against Simion."
Simion is not the only MAGA-style politician seeking election in central Europe.
Karol Nawrocki, the presidential candidate backed by Poland's main nationalist opposition party in a presidential election on May 18, met Trump this week.
If elected, they would expand a cohort of Eurosceptic leaders that already includes the Hungarian and Slovak prime ministers.
"Romania and Poland are two important countries for the United States," Simion told Reuters on Friday.
"We represent partners and we represent allies, both military and politically, to the current (US) administration. This is why it is important for MAGA presidents to be in charge in Bucharest and Warsaw."
Romania's president has a semi-executive role that includes commanding the armed forces and chairing the security council that decides on military aid.
To date, Romania has donated a Patriot air defence battery to Kyiv, is training Ukrainian fighter pilots and has enabled the export of 30 million metric tons of Ukrainian grain through its Black Sea port of Constanta since Russia's invasion.
The country's president can also veto important EU votes and appoints the prime minister, chief judges, prosecutors and secret service heads.
The Trump administration has accused Romania of suppressing political opposition and lacking democratic values after November's election was cancelled on what Vice President JD Vance called "flimsy evidence".
