Penarol, the hosts, had the better chances in front of a crowd of 60,000 but could not take them and must now travel to Brazil next Wednesday to complete the job away from home.
The Uruguayans had their first sight of goal a minute before the break when defender Guillermo Rodriguez could only head a cross straight at goalkeeper Rafael when unmarked.
Dario Rodriguez then fired over the top as the Uruguayans ended the first half strongly.
But they had keeper Carlos Sosa to thank for preventing them from going behind soon after the break as he kept out a Ze Eduardo shot, the same player then heading an Alex Sandro cross narrowly past the far post.
Penarol had a goal disallowed four minutes from time when Diego Alonso was ruled offside.
Penarol forward Alejandro Martinuccio said he believed his side should have taken an advantage into next week's second leg.
"This result is not fair," he said. "Penarol played good football and had some opportunities to score. I hope we can score at least one in Brazil. The second leg will be similar to tonight's game and I hope that is the case because we played much better than Santos."
Goalkeeper Sosa added: "We should have made home advantage count, but Penarol have already recorded good results away from home so anything can happen."
Santos defender Durval, meanwhile, said he was satisfied with the result.
He added on Fox Sports: "We handled the pressure, we did not concede and we hope we can play better in the return match in front of our supporters."see more....
