With more than 90% the votes counted, the 67-year-old billionaire has 37%, electoral officials say.
Piñera, who was president from 2010-14, will now face Socialist contender Alejandro Guillier (23%) in the second round on 17 December.
Incumbent leader Michelle Bachelet is unable to seek re-election under Chile's constitution, says a BBC report.
In all, eight candidates were standing in the presidential race.
On Sunday, voters were also electing all 155 members of the lower house and half of the senate.
Opinion polls had made Piñera favourite to win the vote.
In 2010, he became Chile's first conservative leader since the country's return to democracy, ending two decades of uninterrupted centre-left rule.
During the latest presidential campaign Piñera managed to unite Chile's conservative wing, and enjoys backing of the business community.
He represents the right-wing Chile Vamos coalition.
His victory would mark another shift to the right in South America after the rise of conservative leaders in Argentina, Brazil and Peru.
Piñera's main rival Guillier is a former journalist and is candidate from Bachelet's left-wing Nueva Mayoria coalition.
The 64-year-old pledged to continue a series of liberal reforms launched by Bachelet.