With 40% of votes counted, Castro, the wife of former President Manuel Zelaya, had 53.5%, while Nasry Asfura, candidate of the ruling National Party had 34%, preliminary results from the national electoral council showed.
Castro, 62, was competing in a field of more than a dozen candidates, and supporters hailed a triumph that would end a dozen years of conservative rule and return the left to power for the first time since Zelaya was deposed in a 2009 coup.
Results appeared to be heading to a far clearer result than in the previous election, when irregularities in the vote count sparked deadly protests and led to incumbent President Juan Orlando Hernandez controversially securing a second term.
After polls closed, National Party officials quickly claimed victory after what the electoral council described as an historic turnout. Still, Asfura himself earlier pledged to honor voters' verdict when casting his ballot.
Castro, the opinion polls' leader since tying up with Nasralla in October, sought to unify opposition to Hernandez, who has denied accusations of having ties to powerful gangs, despite an open investigation in the United States linking him to alleged drug trafficking.