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.
Five months after a first attempt to hold the election was cancelled after the first round because of alleged Russian interference in favour of far-right frontrunner Calin Georgescu, since banned from standing again, his heir apparent Simion leads opinion polls, riding a wave of popular anger.
Voting starts at 7am on Sunday and ends at 9pm (4am Monday AEST).
The large contingent of Romanians abroad, where Simion is popular, began voting on Friday, with the early turnout more than twice that of November's cancelled first round.
Simion is polling at around 30 per cent, a comfortable lead but well short of the 50 per cent he needs to avoid a run-off on May 18.
Political analysts said an ultimate victory for Simion could isolate the country, erode private investment and destabilise NATO's eastern flank, where Romania's neighbour Ukraine is fighting a Russian invasion.
Simion's main rivals are two centrists, former senator Crin Antonescu, 65, backed by the three parties in the current pro-Western government, and Bucharest Mayor Nicusor Dan, 55, running as an independent on an anti-corruption platform.
Both are pro-EU and pro-NATO and back Ukraine. Victor Ponta, a former leftist prime minister who has turned conservative nationalist, is ranked fourth but could prove a dark horse.
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."
The Trump administration has accused Romania of suppressing political opposition and lacking democratic values after November's election was cancelled. A team of US observers were in Bucharest for Sunday's vote.
